m 


^^}'MMBMWM^ 


'mm 


MM   li 


;'•  ^IVll'J-iMU 


!!!!  Pi  1 


II 


\m-\ 


V 

! 

i 

I' ,  ' 

1^  •, 


,  I ;    I  ■     1 1    '  I 


\i'\ 


m 


mm 


lilt 


i' ' 


mm ; 


Pil 


f 


lii/ 


iiiii 


, '  1 1  •  ■ 
t  ti' 

f 


^>m\\m\ 


i  ■ '   I 
I  ^1, 


'illii' 


alljp  ^,  p,  pll  pkarg 


1  -J-    »  \  '■ 


QH345 

V4- 


S00290839  V 


Date  Due 

4Af'^V 

5  WiY'25t      1 

-- 

iiL.^r 

'  l.^?^1 

A 

7^-%") 

1/ 

?^ 

4 

1 

1 

! 

L.  B.  Cat. 

No.  1137 

.0 


74-10 


r 


YALE    UNIVERSITY 
MRS.   HEPSA  ELY  SILLIMAN   MEMORIAL  LECTURES 


IRRITABILITY 


SILLIMAN  MEMORIAL  LECTURES 
PUBLISHED  BY  YALE  UNIVERSITY  PRESS 


ELECTRICITY   AND   MATTER.     By  Joseph   John   Thomson,   D.Sc, 
LL.D.,  Ph.D.,  F.R.S.,,  Fellow  of  Trinity  College,  Cambridge,  Cavendish 
Professor  of  Experimental  Physics,  Cambridge. 
Price  $1.25  net;  postage  10  cents  extra. 

THE  INTEGRATIVE  ACTION  OF  THE  NERVOUS  SYSTEM.     By 
Charles   S.   Sherrington,   D.Sc,  M.D.,   Hon.   LL.D.,   Tor.,   F.R.S. ,  Holt 
Professor  of  Physiology  in  the  University  of  Liverpool. 
Price  $3.50  net ;  postage  25  cents  extra. 

RADIOACTIVE  TRANSFORMATIONS.  By  Ernest  Rutherford, 
D.Sc,  LL.D.,  F.  R.  S.,  Macdonald  Professor  of  Physics,  McGill  University. 
Price  $3.50  net;  postage  22  cents. 

EXPERIMENTAL      AND      THEORETICAL      APPLICATION      OF 
THERMODYNAMICS     TO     CHEMISTRY.      By    Walther    Nernst, 
Professor   and   Director   of   the   Institute   of  Physical   Chemistry   in    the 
University  of  Berlin. 
Price  $1.25  net;  postage  10  cents  extra. 

PROBLEMS    OF    GENETICS.     By    William    Bateson,    M.A.,    F.R.S., 

Director  of  the  John  Innes  Horticultural  Institution,  Merton  Park,  Surrey, 

England. 

Price  $4.00  net;  postage  23  cents  extra. 

STELLAR      MOTIONS.      WITH      SPECIAL      REFERENCE      TO 
MOTIONS     DETERMINED     BY     MEANS     OF     THE     SPECTRO- 
GRAPH.   By  William  Wallace  Campbell,  Sc.D.,  LL.D.,  Director  of  the 
Lick  Observatory,  University  of  California. 
Price  $4.00  net;  postage  23  cents  extra. 

THEORIES  OF  SOLUTION.     By  Svante  August  Arrhenius.  Ph.D., 
Sc.D.,  M.D.,  Director  of  the  Physico-Chemical  Department  of  the  Nobel 
Institute,  Stockholm,  Sweden. 
Price  $2.25  net;  postage  14  cents  extra. 

IRRITABILITY,   A   PHYSIOLOGICAL  ANALYSIS   OF   THE  GEN- 
ERAL EFFECT  OF  STIMULI  IN  LIVING  SUBSTANCE.     By  Max 
Verworn,  M.D.,  Ph.D.,  Professor  at  Bonn  Physiological  Institute. 
Price  $3.50  net;  postage  20  cents  extra. 


IRRITABILITY 

A  PHYSIOLOGICAL  ANALYSIS  OF  THE  GENERAL 
EFFECT  OF  STIMULI  IN  LIVING  SUBSTANCE 


BY 


MAX  VERWORN,  M.D.,  Ph.D. 

Professor  at  Bonn  Physiological  Institute 


WITH  DIAGRAMS  AND  ILLUSTRATIONS 


New  Haven:  Yale  University  Press 

London  :    Henry  Frowde 

Oxford  University  Press 

MCMXIII 


COPYRIGHT,  1913 
By  YALE    UNIVERSITY   PRESS 


First  Printed  May,  1913,  600  Copies 


THE  SILLIMAN  FOUNDATION. 

In  the  year  1883  a  legacy  of  eighty  thousand  dollars  was  left 
to  the  President  and  Fellows  of  Yale  College  in  the  city  of  New 
Haven,  to  be  held  in  trust,  as  a  gift  from  her  children,  in  memory 
of  their  beloved  and  honored  mother,  Mrs.  Hepsa  Ely  Silliman. 

On  this  foundation  Yale  College  was  requested  and  directed  to 
establish  an  annual  course  of  lectures  designed  to  illustrate  the 
presence  and  providence,  the  wisdom  and  goodness  of  God,  as 
manifested  in  the  natural  and  moral  world.  These  were  to  be 
designated  as  the  Mrs.  Hepsa  Ely  Silliman  Lectures.  It  is  the 
belief  of  the  testator  that  any  orderly  presentation  of  the  facts 
of  nature  or  history  contributed  to  the  end  of  this  foundation 
more  effectively  than  any  attempt  to  emphasize  the  elements  of 
doctrine  or  creed ;  and  he  therefore  provided  that  lectures  on 
dogmatic  or  polemical  theology  should  be  excluded  from  the  scope 
of  this  foundation,  and  that  the  subjects  should  be  selected  rather 
from  the  domains  of  natural  science  and  history,  giving  special 
prominence  to  astronomy,  chemistry,  geology^  and  anatomy. 

It  was  further  directed  that  each  annual  course  should  be  made 
the  basis  of  a  volume  to  form  part  of  a  series  constituting  a 
memorial  to  Mrs.  Silliman.  The  memorial  fund  came  into  the 
possession  of  the  corporation  of  Yale  University  in  the  year  1901 : 
and  the  present  volume  constitutes  the  ninth  of  the  series  of 
memorial  lectures. 


^'Ho^nry 


M»«KSIS«,,    '"^"' 


PREFACE 

The  lectures  on  irritability  here  published  were  held  at  the 
University  of  Yale  in  October,  1911.  When  the  authorities  of 
that  University  honored  me  by  an  invitation  to  give  a  course  of 
Silliman  memorial  lectures,  I  accepted  with  the  more  pleasure  as 
it  furnished  me  with  the  opportunity  of  summarizing  the  results  of 
numerous  experimental  researches  carried  out  with  the  assist- 
ance of  my  co-workers  during  the  course  of  more  than  two 
decades  in  the  physiological  laboratories  of  Jena,  Gottingcn  and 
Bonn,  to  unite  therewith  the  results  obtained  by  other  investi- 
gators and  thus  present  a  uniform  exposition  of  the  general  effects 
and  laws  of  stimulation  in  the  living  substance.  I  have  long 
entertained  this  plan  and  this  for  the  following  reason : 

The  physiologist,  the  zoologist,  the  l)otanist,  the  psychologist, 
the  pathologist,  have  to  deal,  day  in,  day  out,  with  the  effects  of 
stimulation  on  the  living  substance.  No  living  substance  exists 
without  stimulation.  In  the  vital  manifestations  of  all  organisms 
the  interplay  of  the  most  varied  stimuli  produces  an  enormous 
and  manifold  variety  of  effects.  Experimental  biological  science 
employs  artificial  stimulation  as  the  most  important  aid  in  the 
methodic  production  of  certain  effects  of  stimulation.  The  num- 
ber of  researches  in  which  special  effects  of  stimulation  are 
treated  is  endless.  Nevertheless  the  systematic  investigation  of 
the  effects  of  stimulation  have,  curiously  enough,  been  strangely 
neglected.  Although  countless  results  of  individual  effects  of 
stimulation  have  been  studied,  the  attempt  has  never  been  made 
to  establish  a  general  physiology  of  the  laws  of  stimulation  and 
consider  it  as  an  independent  problem.  This  circumstance  induced 
me  to  systematically  investigate  the  general  laws  of  the  effect  of 
stimulation.  In  the  fifth  and  sixth  chapters  of  my  book  on 
general  physiology  the  results  of  these  studies  are  recorded  for 
the  first  time.  Since  then,  especially  during  our  own  researches 
on  the  general  physiology  of  the  nervous  system,  a  great  number 


viii  PREFACE 

of  new  facts  of  importance  for  the  general  physiology  of  the 
effects  of  stimulation  have  been  obtained.  All  these  results  I 
have  endeavored  to  combine  and  elucidate  in  the  following 
lectures. 

The  text  of  the  lectures  in  its  present  form  was  written  in 
German  in  1911.  The  English  translation  was  made  by  my  wife, 
with  the  help  of  our  friend,  Dr.  Lodholz  of  the  University  of 
Pennsylvania,  who  also  undertook  the  reading  of  the  proofs. 
We  wish  here  to  thank  him  once  again  and  express  our  deep 
appreciation  of  the  great  sacrifice  of  time  and  labor  involved  in 
this  task.  I  am  likewise  much  indebted  to  Dr.  Julius  Veszi  for 
his  assistance  unstintingly  given,  especially  in  obtaining  a  number 
of  curves.  Finally,  I  wish  to  take  this  opportunity  to  render 
warmest  thanks  to  the  authorities  of  Yale  University,  and  espe- 
cially to  President  Hadley  and  Professor  Chittenden,  as  well  as 
to  my  special  colleagues,  for  the  hospitality  and  cordial  reception 
extended  to  me  in  New  Haven  and  for  the  pleasant  hours  I  was 
privileged  to  spend  in  their  midst. 

Max  Verworn. 

Bonn. 

Physiological  Laboratory  of  the  University. 


CONTENTS 


Contents:  Introductory.  Earliest  period.  Francis  Glisson  as  founder 
of  the  doctrine  of  irritability.  Alhrecht  von  Haller.  The  vitalists. 
Borden  and  Barthez.  John  Brown's  system.  Johannes  Midler 
and  the  specific  energy  of  living  substance.  Rudolf  Virchoufs 
doctrine  of  the  irritability  of  the  cell.  Discovery  of  the  inhibitory 
effects  of  stimulation.  Weber,  Schiff,  Goltz,  Setschenow,  Sher- 
rington. Claude  Bernard  studies  on  narcosis.  Tropisms.  Ehren- 
herg,  Engelmann,  Pfcffer,  Strasshnrger,  Stahl.  Semons  specu- 
lations on  mneme 


II 

Contents:  Principles  of  scientific  knowledge  and  research.  Origin 
and  meaning  of  the  conception  of  cause.  Cause  and  condition. 
Criticism  of  the  conception  of  cause.  The  conditional  point  of 
view.  Conception  of  cause.  The  conditional  point  of  view  applied 
to  the  investigation  of  life.  Conception  of  vital  conditions.  Defi- 
nition of  the  conception  of  stimulation 18 

III 

Contents:  The  quality  of  the  stimulus.  Positive  and  negative  altera- 
tions of  the  factors  which  act  as  vital  conditions.  Extent  of  the 
alteration  in  vital  conditions  or  intensity  of  the  stimulus.  Thresh- 
old stimuli,  sub-threshold,  submaximal,  maximal  and  supermaxi- 
mal  intensities  of  stimulus.  Relations  between  the  intensity  of 
stimulus  and  the  amount  of  response.  The  Weber  and  Fechner 
law.  All  or  none  law.  Time  relations  of  the  course  of  the 
stimulus.  Form  of  individual  stimulus.  Absolute  and  relative 
rapidity  in  the  course  of  the  stimulus.  Duration  of  the  stimulus 
after  reaching  its  highest  point.  Adaptation  to  persistent  stimuli. 
Series  of  individual  stimuli.  Rhythmical  stimuli.  The  Ncrnst 
law ^^ 


X  CONTENTS 

IV 

Contents:  Various  examples  of  the  effects  of  stimulation.  Metab- 
olism of  rest  and  metabolism  of  stimulation.  Metabolic  equilib- 
rium. Disturbances  of  equilibrium  by  stimuli.  Quantitative  and 
qualitative  alterations  of  the  metabolism  of  rest  under  the  influ- 
ence of  stimuli.  Excitation  and  depression.  Specific  energy  of 
living  substance.  Qualitative  alterations  of  the  specific  metab- 
olism and  their  relations  to  pathology.  Functional  and  cytoplastic 
stimuli.  Relations  of  the  cytoplastic  effects  of  stimuli  to  the  func- 
tional. Hypertrophy  of  activity  and  atrophy  of  inactivity.  Meta- 
bolic alterations  during  growth  of  the  cell.  Primary  and  second- 
ary effects  of  stimulation.    Scheme  of  effects  of  stimulation.     .     .65 

V 

Contents:  Indicators  for  the  investigation  of  the  process  of  excitation. 
Latent  period.  The  question  of  the  existence  of  assimilatory  exci- 
tations. Dissimilatory  excitations.  Excitations  of  the  partial 
components  of  functional  metabolism.  Production  of  energy  in 
the  chemical  splitting  up  processes.  Oxydative  and  anoxydative 
disintegration.  Theory  of  oxydative  disintegration.  Dependence 
of  irritability  on  oxygen.  Experiments  on  unicellular  organisms, 
nerve  centers  and  nerve  fibers.  Restitution  after  disintegration  by 
metabolic  self-regulation.  Organic  reserve  supplies  of  the  cell. 
The  question  of  a  reserve  supply  of  oxygen  of  the  cell.  Metabolic 
self-regulation  as  a  form  of  the  law  of  mass  effect,  and  metabolic 
equilibrium  as  a  condition  of  chemical  equilibrium.  Functional 
hypertrophy 87 

VI 

Contents:  Only  processes  of  excitation  are  conducted,  not  processes  of 
depression.  Conduction  of  excitation  in  its  two  extreme  instances. 
Conduction  in  undifferentiated  pseudopod  protoplasm  of  rhizopoda. 
Conduction  of  excitation  with  decrement  of  intensity  and  rapidity. 
Conduction  of  excitation  in  the  nerve.  Rapidity  of  conduction. 
Conduction  of  excitation  without  decrement.  Relation  between 
irritability  and  conductivity.  Conduction  of  excitation  with  decre- 
ment of  the  nerve  after  artificial  depression  of  irritability  by  nar- 
cosis. Theory  of  the  decrementless  conduction  of  the  normal 
nerve.  Proof  of  the  validity  of  the  "all  or  none  law"  in  the 
medullated  nerve.  Theory  of  the  process  of  the  conductivity  of 
excitation.  Theory  of  core  model  (Kernleiter).  Electrochemical 
theory  of  conduction  based  on  the  properties  of  semi-permeable 
surfaces 118 


CONTENTS  xi 

VII 

Contents:  Conception  of  specific  irritability.  Alteration  of  specific 
irritability  during  and  after  excitation.  Refractory  period  in 
various  forms  of  living  substance.  Absolute  and  relative  refrac- 
tory period.  Curve  of  irritability  during  refractory  period. 
Dependence  of  the  duration  of  the  refractory  period  on  the 
rapidity  of  the  course  of  the  metabolic  processes  in  the  living 
substance.  Dependence  on  temperature.  Dependence  on  supply 
of  oxygen.  Theory  of  refractory  period.  Refractory  period  as 
basis  of  fatigue.  Fatigue  as  a  form  of  asphyxiation.  Alterations 
of  irritability  and  the  course  of  excitation  in  fatigue.  Recovery 
from  fatigue.  The  role  played  by  oxygen  in  recovery.  Fatigue 
as  an  expression  of  the  prolongation  of  the  refractory  period 
conditioned  by  the  relative  want  of  oxygen.    Fatigue  of  the  nerve.  154 


VIII 

Contents:  Examples  of  effects  of  interference  of  stimuli  in  unicellular 
organisms.  Interference  of  galvanic  and  thermic  stimuli  in  Para- 
mecia.  Interference  of  galvanic  and  thermic  stimuli  and  narcotics. 
Interference  of  galvanic  and  mechanical  stimuli.  Interference  of 
galvanotaxis  and  thigmotaxis  in  Paramecia  and  hypotin  infusoria. 
Real  or  homotop  interference,  apparent  or  heterotop  interference. 
The  two  effects  of  homotop  interference  of  excitations :  Summa- 
tion and  inhibition  of  excitations.  Theory  of  the  processes  of 
inhibition.  Hering-Gaskell  Theory.  Inhibition  as  an  expression 
of  the  refractory  period.  Individual  possibilites  of  interference 
of  two  stimuli.  Interference  of  an  excitating  and  a  depressing 
stimulus.  Interference  of  two  depressing  stimuli.  Interference 
of  two  excitating  stimuli.  Analysis  of  the  interference  of  two 
excitations.  Interference  of  two  single  stimuli.  Conditions  upon 
which  the  result  of  interference  is  dependent.  Heterobole  and 
isobole  living  systems.  Intensity  of  the  two  stimuli.  Interval 
between  the  stimuli.  Specific  irritability  and  rapidity  of  reaction 
of  the  living  system.  Latent  period.  Interference  of  single  stim- 
uli in  a  series.  General  scheme  of  the  development  of  the  effect 
of  interference.  Summation  and  inhibition.  Apparent  increase  of 
irritability.  Conditions  of  summation.  Tonic  excitations.  Condi- 
tions of  inhibitions.  Various  types  of  inhibition.  Interference  of 
two  series  of  stimuli.  Relations  in  the  nervous  system.  Peculiari- 
ties of  the  nerve  fibers.  Conversion  of  the  nerve  by  relative 
fatigue  from  an  isobolic  into  a  heterobolic  system 189 


xii  CONTENTS 

IX 

Contents:  Necessity  of  cellular  physiological  analysis  of  toxic  depres- 
sions by  pharmacology.  Apparent  variety  of  processes  of  depres- 
sion. Depression  of  oxydative  disintegration  as  the  most  extended 
principle  in  the  processes  of  depression.  Asphyxiation,  fatigue, 
heat  depression,  as  a  consequence  of  restriction  of  oxydative  dis- 
integration. Narcosis.  Theories  of  narcosis.  The  alteration  of 
specific  irritability  and  conductivity  in  narcosis.  Depression  of 
oxydative  processes  in  narcosis.  Asphyxiation  of  living  substance 
when  oxygen  is  present  during  narcosis.  Persistence  of  anoxyda- 
tive  disintegration  in  narcosis.  Increase  of  the  same  by  stimuli. 
Depression  by  narcosis  as  a  form  of  acute  asphyxiation.  Hypothe- 
sis on  the  mechanism  of  depression  of  oxygen  exchange  by  nar- 
cotics. Possibility  of  combining  the  facts  with  the  observations  of 
Meyer  and  Overton 235 


IRRITABILITY 


CHAPTER   I 


THE  HISTORY  OF  THE  SUBJECT 


Contents:  Introductory.  Earliest  period.  Francis  Glisson  as  founder  of 
the  doctrine  of  irritability.  Albrecht  von  Haller.  The  vitalists.  Bor- 
deu  and  Barthez.  John  Brown's  system.  Johannes  Miiller  and  the 
specific  energy  of  living  substance.  Rudolf  Virchows  doctrine  of  the 
irritability  of  the  cell.  Discovery  of  the  inhibitory  effects  of  stimu- 
lation. Weber,  Schiff,  Goltz,  Setschenow,  Sherrington.  Claude  Ber- 
nard studies  on  narcosis.  Tropisms.  Ehrenherg,  Engelmann,  Pfcffer, 
Strassbnrger,  Stahl.    Semon's  speculations  on  mneme. 

Irritability  is  a  general  property  of  living  substance  but  not 
exclusively  so.  Irritable  systems  also  exist  in  inanimate  nature. 
What  characterizes  living  substances  is  not  irritability  as  such, 
but  an  irritability  of  a  specific  type.  The  irritability  of  the  living 
system  can,  therefore,  not  be  studied  alone,  but  as  the  properties 
of  a  living  system  are  dependent  upon  each  other,  so  this  property 
must  be  considered  with  the  others  possessed  by  a  living  sub- 
stance. In  this  sense  irritability  presents  a  problem  of  funda- 
mental physiological  importance.  For  if  we  could  analyze  tlie 
irritability  of  living  substance  to  its  essence,  then  the  nature  of 
Hfe  itself  would  be  fathomed.  The  analysis  of  irritability  of 
living  substance  offers  us,  therefore,  a  path  to  the  investigation 
of  life  and  herein  lies  the  importance  of  the  study  of  irritability. 

I  wish  to  follow  this  path  toward  the  knowledge  of  the  vital 
processes  and  to  endeavor  to  show  in  these  lectures  what  informa- 
tion the  analysis  of  irritability  and  that  of  the  effect  of  stimuli 
can  give  us  of  the  mechanism  of  the  processes  in  living  substance. 
Before  doing  so,  however,  I  wish  to  consider  somewhat  more  in 
detail  the  question  as  to  how  we  have  arrived  at  the  conception 
of  the  nature  of  irritability. 


2  IRRITABILITY 

To  the  thinkers  both  in  the  field  of  physiology  and  medicine  of 
ancient  and  mediaeval  times  the  conception  of  irritability  was 
quite  foreign.  Even  a  com_prehension  of  the  nature  of  stimuli 
had  not  yet  begun  to  crystallize  from  vague  impressions  of  the 
various  influences  of  different  agents  on  the  human  being. 
Nevertheless  they  knew  of  such  influences  of  the  most  varying 
kinds  upon  the  human  body.  The  ancients  already  possessed 
a  materia  medica,  founded  on  the  real  or  supposed  influence  of 
various  mineral,  vegetable  and  animal  substances  upon  the  organ- 
ism. It  was  also  known  that  heat  and  cold,  light  and  darkness 
had  an  effect  upon  disease.  They  likewise  believed  in  the  influ- 
ence of  certain  factors  upon  the  health  of  man,  which  in  reality 
have  no  effect  whatsoever,  as  the  stars  and  the  magnet.  But 
neither  in  ancient  nor  in  mediaeval  times  was  the  state  of  knowl- 
edge reached  wherein  generalizations  were  made  from  these 
agents,  which  had  a  real  or  supposed  action  upon  the  organism, 
and  to  combine  these  to  a  general  conception  of  stimulation. 

The  conception  of  stimulation  and  irritability  cannot  however 
be  separated. 

The  founder  of  the  doctrine  of  the  irritability  of  living  sub- 
stance is  Francis  Glisson  (1597-1677),  member  of  the  Collegium 
Medicum  in  London  and  at  the  same  time  Professor  in  Cam- 
bridge. It  is  a  fact  also  not  altogether  without  interest,  that 
Glisson  at  the  same  time  was  in  a  certain  sense  a  forerunner  of 
those  who  interpreted  nature  from  a  physical  standpoint.  Glisson 
as  an  anatomist  and  physiologist  was  an  excellent  observer  and 
experimenter,  but  the  most  prominent  trait  of  his  character 
was  his  inclination  to  philosophic  observation  and  analysis  of 
nature.  His  ''Tractatus  de  natura  suhstantice  energetica"'^  must, 
therefore,  be  considered  as  the  chief  work  of  his  life.  In  this 
voluminous  book  Glisson  develops  an  entire  system  of  natural 
philosophy,  which  in  accord  with  the  character  of  the  philosophy 
of  that  time  is  unfortunately  of  an  absolutely  speculative  nature 
and  which  had  hardly  emancipated  itself  from  the  scholasticism 

1  Franciscus  Glissonius :  "Tractatus  de  natura  substantiae  energetica  seu  de  vita 
natura  ej usque  tribus  primis  facultatibus  perceptiva,  appetitiva,  motiva,"  etc.  Londini 
M  D  C  L  XXII. 


THE  HISTORY  OF  THE  SUBJECT  3 

of  the  preceding  period  of  thought.  When  the  ideas  of  Glisson 
are  isolated  from  the  wilderness  of  scholastic  phraseology,  the 
system  is  somewhat  as  follows.  The  basis  of  all  existence, 
"substance,"  has  according  to  him  two  general  properties,  its 
"fundamental  subsistence/'  that  is,  the  essence  of  its  being,  and 
its  "energetic  subsistence/'  that  is,  the  essence  of  its  activity.  To 
these  are  added  the  properties  possessed  in  specific  cases,  that  is, 
its  ''additional  subsistence/'  The  energetic  subsistence  forms  the 
basis  of  all  life.  Life  is  therefore  present  not  only  in  organic 
nature,  but  in  all  nature  which  is  characterized  by  the  union  of 
the  general  energetic  subsistence  with  the  special  additional  sub- 
sistence of  an  animal  and  vegetable  nature.  In  other  forms  of 
life  in  nature  the  energetic  subsistence  is  combined  with  other 
special  forms  of  the  additional  subsistence.  The  universal 
essence  of  all  life,  that  is  the  energetic  subsistence,  has  only  three 
fundamental  faculties :  the  "appetitiva/'  the  "perceptiva"  and  the 
"motiva/'  The  modus  is  the  result  of  a  "perceptio/'  but  the 
"perceptio"  is  not  thinkable  unless  the  object  has  the  "appetitus" 
to  receive  the  external  influence.  Glisson's  doctrine  of  irritability 
is  based  on  this  conception,  which  he  develops  in  a  second  work 
already  begun  before  the  "Tractatus  de  natura  substanticc/'  but 
not  finished  until  later  and  only  published  after  his  death.  In 
this  "Tractatus  de  ventriculo  et  intestinis/'^  Glisson  dwells  in 
detail  on  the  physiological  properties  of  animal  structures  and 
develops  for  the  first  time  his  conception  of  irritability  in  the 
chapter  "De  irritabilitate  fibrarum."  The  "irritability"  manifests 
itself  in  the  appearance  of  the  alteration  of  movement,  which  is 
brought  about  by  external  influences  on  the  animal  structure,  for : 
''Motiva  fibrarum  facultas  nisi  irritabilis  forct,  vcl,  pcrpctuo 
quiesceret,  vet  perpetuo  idem  ageret."  The  fundamental  factor  of 
this  irritability  Glisson  attributes  to  the  "perccptio/^  which  he  dis- 
tinguishes as  a  "perceptio  naturalis,  sensitira  and  animalis." 
The  want  of  clearness  produced  here  by  Glisson's  artificial  distinc- 
tions and  mode  of  expression  is  in  part  removed  if  we  endeavor 

1  Franciscus  Glissonius:  "Tractatus  de  ventriculo  et  intestinis  cui  praemittitur  alius 
de  partibus  continentibus  in  genere  et  in  specie  de  iis  abdominis."  Amstelodami  M  D 
C  L  XXVII. 


4  IRRITABILITY 

to  transfer  his  meaning  into  our  present  methods  of  thought. 
This  distinction  would  then  simply  point  out  the  different  means 
by  which  the  stimuli  can  reach  the  irritable  structures.  The  ''Per- 
ceptio  naturalis"  is  that  which  today  we  should  call  "direct 
response"  to  stimulation,  that  is,  the  excitation  of  the  fiber  by 
artificial  stimuli  applied  directly  to  the  tissue.  Glisson  shows 
here,  that  the  intestines  and  muscles  in  the  body  immediately 
after  death  and  even  when  removed  from  the  body  can  be 
stimulated  to  movement  by  means  of  corrosive  fluids  or  cold. 
The  "Perceptio  sensitiva"  is,  according  to  Glisson,  the  excitation 
of  the  fibers  by  external  stimuli  which  act  on  the  intact  body  as 
a  whole  by  way  of  the  sensory  nerves.  The  ''Perceptio  ah  appe- 
titu  animali  regulata"  finally  is  the  excitation  by  inner  stimuli 
proceeding  from  the  brain.  The  Perceptio  naturalis  is  possessed 
by  all  parts  of  the  body,  even  the  fluids,  the  bones  and  the  fat. 
All  of  them  are  irritable.  But  a  "vitale"  and  a  special  ''animal" 
irritability  they  do  not  possess  to  a  perceptible  degree.  These 
forms  of  irritability  belong  only  to  the  special  parts  of  the  body. 
Here,  however,  the  distinctions  made  by  Glisson  are  quite  vague 
and  contradictory.  In  his  ''Tractatus  de  ventriculo  et  intestinis" 
Glisson  sharply  distinguishes  the  '^sensatio"  from  the  "perceptio." 
The  perceptio  in  itself  is  not  a  sensation,  for  although  individual 
organs  of  the  body  are  irritable,  as  they  all  possess  a  "perceptio," 
they  are  not  in  themselves  sensitive.  The  ''sensatio/'  the  sensa- 
tion, only  arises  when  the  external  ''perceptio"  of  the  individual 
organs  combine  through  the  nerves  with  the  internal  "perceptio" 
of  the  brain.  "Nisi  enim  percepto  externa  ah  interna  simiil  per- 
cipiatnr,  non  est  cognitio  sensitiva  completa."  Sensitivity  is, 
therefore,  a  special  faculty,  that  is  only  based  upon  'irritability. 
I  have  treated  the  views  of  Glisson  somewhat  in  detail  for 
on  the  one  hand  this  seemed  to  me  to  be  only  due  to  the  founder 
of  the  doctrine  of  irritability,  and  on  the  other  we  have 
here  for  the  first  time,  although  in  somewhat  vague  and  little 
worked  out  form,  the  discovery  of  a  general  property  of  all 
living  substance,  and  its  fundamental  importance  for  the  life 
of  the  organisms.  One  might,  therefore,  in  a  certain  sense,  date 
from   Glisson  the  beginning  of  general  physiology,  and  all  the 


THE  HISTORY  OF  THE  SUBJECT  5 

more  so,  because  Glisson  from  the  very  first  connected  the  irri- 
tability of  the  Hving  substance  through  its  i)ossessing  universal 
energy  with  the  phenomena  in  nature  generally,  just  as  we  do 
today  two  hundred  years  after,  on  the  basis  of  the  modern  teach- 
ings of  energy. 

It  might  appear  strange  that  a  teaching  of  such  fundamental 
importance  as  that  of  Glisson  s  theory  of  irritability  was  not  at 
once  accepted  on  all  sides  and  further  developed.  There  were 
two  reasons,  however,  which  prevented  this.  l''irstly,  Glisson  did 
not  devote  himself  to  his  post  of  teacher  at  the  University  of 
Cambridge  with  any  particular  zeal  and  so  consequently  did  not 
establish  a  school  of  his  own,  to  further  work  out  and  develo]) 
his  ideas.  Secondly,  his  doctrines  were  so  speculative  and  ditVi- 
cult  to  understand,  his  differentiations  and  definitions  so  artificial 
and  labored,  that  it  required  the  greatest  effort  to  penetrate  to 
his  fundamental  conceptions  and  so  it  happened  that  Glisson' s 
theory  of  irritability  received  attention  only  at  a  comparatively 
late  date.  Even  then,  of  his  speculative  theories  hardly  more  than 
the  name  ''doctrine  of  irritability"  was  adopted.  Since  the  middle 
of  the  eighteenth  century  this  name,  however,  was  destined  to  lead 
to  excited  controversies. 

The  first  attempt  to  give  Glissoii's  expression  "irritability"  a 
more  concrete  meaning  was  made  by  Holler  (1708-1777)^ 
Unfortunately,  though,  he  confined  this  conception  solely  to 
muscles,  in  that  he  understood  by  the  term  irritability  "the  capa- 
bility of  the  muscles  to  contract,  when  stinuilated.  as  the  result 
of  vital  force  {vi  viva).''  He,  therefore,  applied  the  term  "irri- 
tabihty"  to  that  which  we  today  refer  to  as  "contractility." 
On  the  other  hand  he  applied  the  term  contractility  solely  to  a 
property  possessed  by  other  living  and  dead  animal  as  well  as 
vegetable  matter,  elasticity,  that  is,  the  capabihty  to  resume  its 
original  form  after  distortion.  He  makes  a  sharp  distinction 
between  "irritability,"  which  manifests  itself  by  a  contraction  of 
the  muscles  after  stimulation  by  its  own  vital  force  (vi  viva), 
and  the   "sensitivity,"   which   is   possessed  only   by   the   nervous 

I  Albrecht  v.  Holier:  "Elementa  Physiologix  corporis  humani."  Tomus  IV. 
Lausannae  M  D  C  L  XVI. 


6  IRRITABILITY 

system.  ''Sola  fibra  miiscularis  contrahitur  vi  viva;  sentit  solus 
nervus  et  qua;  nervos  acciperunt  animales  partes/'  By  confining 
the  conception  of  irritability  to  a  single  living  substance,  the 
muscle,  Haller's  theory  represents  a  great  regression  in  compari- 
son to  the  correct  fundamental  thoughts  of  Glisson.  This  unfor- 
tunate use  of  the  term  of  ''irritability,"  "contractility"  and 
"sensitivity"  has  opened  wide  the  gates  to  confusion  and  mis- 
understanding. This  confusion  was  still  further  augmented  by 
the  fact  that  the  vitalistic  school  of  Montpelier  confused  the  idea 
of  vital  force  with  that  of  irritability.  In  the  works  of  Bordeu 
(1722-1776)  these  views  are  comparatively  clear,  if  one  bears 
in  mind  that  he  substitutes  Glisson  s  term  of  "irritability''  with 
that  of  ''sensitivity/'  He  assumes  a  "sensibilite  generale"  or  a 
common  property  of  all  living  structures,  both  solid  and  fluid. 
Besides  this,  each  different  part  has  according  to  him  its  "sensi- 
bilite propre/'  Here  in  place  of  the  clear  conception  of  irri- 
tability we  find  one  of  more  or  less  mythical  nature  possessing 
traces  of  StahVs  "anima."  Nevertheless  we  observe  here  the 
idea  that  all  living  organisms  possess  in  common  a  capability  to 
respond  to  stimuli.  Even  though  Borden  s  differentiation  of  the 
"sensibilite  propre"  and  the  "sensibilite  generale"  is  too  artificial 
and  the  coexistence  of  both  not  justifiable,  his  discussion  of  the 
"sensibilite  propre"  shows  that  he  is  already  on  the  track  of  the 
characteristics  of  the  effect  of  stimuli  which  only  later  under  the 
name  of  "specific  energy"  was  clearly  recognized  as  a  funda- 
mental property  of  all  living  substance.  On  the  other  hand  the 
celebrated  pupil  of  Bordeu,  Barthez  (1734-1806),  accepted  the 
existence  of  a  meaningless  vital  principle,  the  "principe  vitale," 
governing  all  vital  manifestations.  The  two  forms  of  vital  force 
of  all  living  substances,  the  "forces  sensitives"  and  the  "forces 
motrices,"  were  according  to  his  views  manifestations  of  this 
vital  principle.  He  differentiates  the  "force  sensitive"  into  a 
"sensibilite  avec  perception^  and  "sensibilite  sans  perception", 
using  the  term  sensibility  in  the  sense  adopted  by  Bordeu  and 
which  today  we,  with  Glisson,  call  irritability. 

In  this  way  serious  thinkers  of  that  time  trifled  with  the  words 
irritability,    sensitivity,    contractility,    perception.      This    led    to 


THE  HISTORY  OF  THE  SUBJECT  7 

futile  conceptions,  which  equalled  the  phantasies  of  the  worst 
period  of  speculative  philosophy  and  which  in  no  way  led  to 
progress.  Hence  it  is  easy  to  understand  that  numerous  attempts 
were  made  in  those  days  to  reconcile  in  some  way  these  different 
conceptions.  An  explanation,  wdiich  was  the  beginning  of  fur- 
ther development,  came  from  England  in  the  works  of  John 
Brozvn  (1735-1788),^  a  man  who  was  as  talented  as  he  was  dis- 
solute. Brozvn  was  an  independent  thinker,  not  without  genius, 
w^hose  knowledge  in  practice  and  theory,  however,  was  limited. 
This  combination  in  his  mentality  enabled  him  to  observe  the 
problems  somewhat  differently  than  through  the  glasses  of  the 
usual  conceptions  of  that  time.  In  direct  opposition  to  his  teacher 
Cullen  (1712-1790),  one  of  the  leading  minds  in  the  medical 
school  of  Edinburgh,  who  considered  irritability  only  as  an 
effect  of  sensibility  and  pronounced  the  latter  a  specific  property 
of  the  nervous  system,  Brown  took  the  standpoint  that  all  living 
substance,  vegetable  as  well  as  animal,  in  contrast  to  lifeless 
matter,  possessed  a  fundamental  property  which  he  designated 
as  excitability,  that  is  to  say,  the  capability  of  being  stimulated 
to  specific  vital  manifestations  through  external  factors  or 
''stimuli,"  in  which  sensitivity  and  indeed  all  mental  processes  as 
well  as  movement  are  interpreted  as  specific  eft'ects,  which  the 
"stimuli"  produce  on  the  irritable  organs.  This  was  an  important 
advance  and  from  a  wilderness  of  trifling  conceptions  his  obser- 
vations led  to  a  clearer  knowledge  of  this  subject.  But  Brown 
went  even  further.  In  his  so-called  "theory  of  irritation,"  he 
has  presented  a  whole  system  of  responsivity  to  stimulation,  which 
in  the  first  chapters  of  his  chief  work  he  expounds  with  wonder- 
ful clearness.  The  fundamental  principles  here  established  must 
be  accepted  even  today.  The  essential  basis  of  this  "theory  of 
irritability"  which  he  worked  out  especially  for  his  doctrine  of 
disease,  and  which  has  also  played  an  important  part  in  patliology. 
is  the  following:  Every  living,  that  is,  excitable  system,  is  con- 
tinually influenced  by  stimuli.  The  stimuli  consist  of  either  exter- 
nal factors,  such  as  heat,  food,  foreign  matter,  poisons,  etc., 
or  inner  factors  which  result  from  the  influence  of  the  activity 

1 /o/tn  Brown;  "Elementa  medicinse."     1778.     English  translation.     London   1778. 


8  IRRITABILITY 

of  one  organ  upon  another.  Only  as  a  result  of  the  continual 
action  of  stimuli  is  life  maintained,  in  that  the  stimuli  produce 
continual  "excitement"  in  the  irritable  substance.  The  degree  of 
irritability  differs  in  various  plants,  animals,  in  different  struc- 
tures of  the  body,  and  even  in  the  same  individual  at  differ- 
ent times  under  different  circumstances.  The  strength  of  the 
"excitement"  depends  on  the  one  hand  upon  the  degree  of  irri- 
tability, and  on  the  other  upon  the  strength  of  the  stimulus.  The 
irritability  itself  is  influenced  and  changed  by  the  action  of  the 
stimuli.  If  the  stimuli  are  too  strong  and  are  of  prolonged  dura- 
tion, the  irritability  diminishes  as  a  result  of  exhaustion ;  if  weak 
stimuli  act  during  a  prolonged  time,  the  irritability  increases. 
The  healthy  organism  has  a  mean  degree  of  irritability.  Disease 
occurs  when  this  state  is  altered  by  strong  stimuli  or  by  an 
absence  of  stimulation.  Disease  and  health,  therefore,  differ  not 
qualitatively  but  only  quantitatively.  It  is  here  seen  that  we  have 
the  first  attempt  at  a  systematic  interpretation  of  the  effects  of 
stimulation,  and  it  is  astonishing  how  sharply  and  successfully 
Brown  has  pointed  out  the  foundations  of  this  important  field. 
He  has  in  this  way  not  only  amply  compensated  for  the  great  set- 
back in  the  history  of  the  teaching  of  irritability  produced  by  the 
confusions  of  conceptions  created  by  Holler  and  the  vitalists,  but 
also  placed  the  whole  of  the  physiology  of  stimulation  on  a  firm 
foundation  upon  which  it  is  possible  to  build  further.  Though  it 
is  true  that  many  of  his  special  theories,  in  particular  those  on 
nature  and  the  origin  of  disease,  are  quite  erroneous,  still  a  just 
critic  must  judge  work  in  relation  to  the  period  in  which  it  was 
written,  and  I  question  if  at  the  present  day  the  science  of  medi- 
cine does  not  contain  teachings  which  in  a  hundred  years  will 
also  prove  untenable. 

Johannes  Muller  (1801-1858)  then  added  an  important  stone 
to  the  building  up  of  our  knowledge  of  irritability.  This  was  the 
clear  recognition  of  the  specific  energy  of  living  substances.  We 
have  already  found  the  germ  in  Borden's  term  ''sensibilite  pro  pre" 
or  ''sensibilite  particuliere."  Brown  was  also  of  the  opinion  that 
different  living  objects  possessed  different  types  of  irritability 
and  that  excitation  of  their  special  functions  was  not  dependent 


THE  HISTORY  OF  THE  SUBJECT  9 

upon  the  kind  of  stimulus  acting  upon  them.  Johannes  Miillcr, 
grasping  the  idea  hidden  in  this  presentation,  transformed  it  into 
a  clear  and  fundamental  conception.  Already  in  the  work  written 
in  his  early  years  treating  of  optical  illusions  he  says:^  "It  is 
immaterial  by  which  means  the  muscle  is  stimulated,  whether 
by  galvanism,  chemical  agents,  mechanical  irritation,  inner  organic 
stimuli  or  sympathetic  response  from  quite  different  organs ; 
to  every  means  by  which  it  is  stimulated  and  an  effect  pro- 
duced, it  responds  by  movement.  Movement  is,  therefore,  the 
effect  and  the  energy  of  the  muscle  at  the  same  time."  'Thus 
it  is  throughout  with  all  reactions  in  the  organisms."  'The  sensory 
nerve,  responding  to  any  stimulus  of  whatever  kind,  has  its 
specific  energy;  pressure,  friction,  galvanism  and  inner  organic 
stimuli  produce  in  nerves  of  sight  that  which  is  peculiar  to  them, 
light  sensation;  in  the  nerves  of  hearing,  that  which  is  peculiar 
to  them,  sound  sensation;  and  in  the  nerves  of  touch,  touch 
sensations.  On  the  other  hand,  everything  which  affects  a  secre- 
tory organ  produces  change  of  the  secretion ;  that  which  affects 
the  muscle,  movement.  Galvanism  is  not  superior  to  any  other 
methods,  of  whatever  kind,  which  can  bring  about  stimulation." 
And  in  his  handbook  of  physiology  Johannes  Miiller-  formulates 
the  law  of  specific  energy  for  the  sensory  structures  briefly  in  the 
following  words :  'The  same  external  factor  produces  different 
sensations  in  the  different  senses  according  to  the  nature  of  each 
sense,  namely,  the  sensation  of  the  particular  sensory  nerves ; 
and  the  reverse :  the  characteristic  sensations  peculiar  to  every 
sensory  nerve  can  be  produced  by  several  internal  and  external 
influences."  This  doctrine  of  the  specific  energy  of  the  sense 
substance  possesses  an  importance  which  extends  far  beyond  the 
domain  of  the  physiology  of  stimulation,  for  it  forms  the  basis 
on  which  the  whole  theory  of  human  knowledge  must  be  built 
up,  no  matter  how  it  may  be  constructed  in  detail. 

As  Johannes  Miillcr  already  clearly  emphasizes,  it  is  here  not 

1  Johannes  Miiller:  "tJber  die  phantastischen  Gesichtserscheinungen.  Eine  physiolo- 
gische  Untersuchung  mit  einer  physiologischen  Urkunde  des  Aristotles  iiber  den 
Traum,  den  Physiologen  und  den  Arztcn  gewidmet."     Coblenz   1826. 

2  Johannes  Miiller:  "Handbucli  der  Physiologic  des  Menschen  fiir  Vorlesungen." 
Coblenz   1837. 


10  IRRITABILITY 

the  question  of  a  law  confined  to  the  sense  substance,  but  one 
that  apphes  to  all  living  substances.  Every  living  substance  has 
its  ''specific  energy,"  that  is,  its  characteristic  vital  phenomena 
and  this  is  produced  by  stimuli  of  the  most  varied  kind.  This 
doctrine  received  an  extension  of  inestimable  value  for  its  future 
development  by  the  great  discovery  of  Schleiden,  that  the  cell  is 
the  elementary  building  stone  of  the  plant  organism.  Subse- 
quently Schwann  at  the  instigation  of  Schleiden  made  further 
investigations  and  found  that  this  discovery  applied  also  to  the 
animal  organism.  Irritability  having  been  recognized  as  a  general 
property  of  living  substance,  it  followed  that,  after  the  founda- 
tion of  the  cell  doctrine,  every  cell  must  possess  irritability  and 
have  its  own  specific  energy.  It  now  became  necessary  to  study 
the  manifestations  of  irritability  of  the  cells  in  their  specific  form. 
Strange  to  say,  this  was  done  at  an  earlier  date  in  pathology  than 
in  physiology.  Indeed,  since  the  time  of  Brown  the  study  of  irri- 
tability was  furthered  far  more  by  pathology  than  by  physiology. 
The  chief  reason  for  this  is  probably  the  great  practical  interest 
that  the  investigation  of  disease  possesses,  Brown  having  already 
quite  correctly  ascribed  the  existence  of  disease  to  the  relations 
of  the  organism  or  its  parts  to  stimuli.  Rudolph  Virchow  then, 
after  the  establishment  of  the  cell  doctrine,  arrived  at  the  momen- 
tous conclusion,  that  disease  must  be  considered  as  reactions  of 
the  body  cells  to  stimuli.  In  his  epoch-making  ''Cellular  pathol- 
ogic,"^ he  has  carried  out  this  idea  in  a  classical  manner.  By  irri- 
tability Virchozv  understands  "a  property  of  the  cells,  by  virtue 
of  which  they  are  set  into  activity,  when  afifected  by  external 
influences."  There  are,  however,  various  kinds  of  actions  which 
can  be  brought  about  by  external  influences.  But  essentially  there 
are  three  kinds.  The  effects  produced  are  functional,  nutritive, 
formative.  The  result  of  excitation,  or  if  one  will,  of  stimulation 
of  a  living  part,  can,  therefore,  according  to  circumstances,  be 
either  merely  a  functional  process,  or  there  can  be  a  more  or  less 
intense  nutritive  activity  produced  without  the  function  being 
necessarily  at  the  same  time  activated,  or  finally,  it  is  possible 

1  Rudolph     Virchow:    Die    Zellularpathologie    in    ihrer    Begrundung    auf    physiolo- 
gische  und  pathologische  Gewebelehre.     1  Aufl.  Berlin  1858 — 4  Aufl.  1871. 


THE  HISTORY  OF  THE  SUBJECT  11 

that  a  process  of  formative  change  may  occur  wliich  prociuces 
new  elements  in  greater  or  less  numbers.  V  ire  how  touches  here 
for  the  first  time  upon  a  question  of  extraordinary  moment,  the 
important  bearings  of  which  have  only  now  begun  to  be  recog- 
nized and  seriously  considered.  We  now  know,  for  example, 
that  the  functional  excitation  can  be  separated  to  a  certain  degree 
from  the  cytoplastic  excitation  of  the  muscle.  If  the  muscle  is 
acted  upon  by  functional  stimuli,  the  excitation  takes  place  mainly 
in  the  form  of  functional  metabolism,  nitrogen-free  substances 
are  broken  down  in  increased  quantities,  whereas  cytoplastic 
metabolism,  which  produces  more  profound  alteration  in  the  living 
substance,  and  which  goes  so  far  as  to  bring  about  a  breaking 
down  and  building  up  of  the  nitrogen  containing  atom  grouj)s.  is 
hardly  at  all  increased.  It  would  be  an  error,  however,  to  look 
upon  these  different  kinds  of  metabolism  as  quite  indei)endent. 
Considering  the  close  correlation  which  all  the  phases  of  metal)- 
olism  bear  to  each  other,  this  idea  cannot  well  be  entertained. 
If,  however,  we  question  in  what  manner,  for  instance,  the 
functional  and  the  cytoplastic  metabolism  are  linked  together, 
we  have  a  problem  before  us  which  does  not  belong  to  the  past, 
but  to  the  present  and  future.  Indeed,  Virchoiv  seems  already  to 
have  felt  that  a  sharp  division  between  the  different  ])hases 
and  parts  of  functional  metabolism  in  the  cell  does  not  exist,  for 
he  says:  "It  is  true  that  it  cannot  be  denied  that,  especially  be- 
tween the  nutritive  and  formative  processes  and  likewise  between 
the  functional  and  nutritive,  intermediate  gradations  occur."  Still 
they  differ  essentially  in  their  characteristic  action  and  in  the 
internal  alterations  which  the  stimulated  part  undergoes,  depend- 
ing on  whether  it  functionates,  nourishes  itself,  or  is  the  seat  of 
special  growth.  Disease  consists  of  the  influence  of  stimuli  upon 
these  physiological  processes.  The  law  of  the  specific  energy  of 
living  substance  is  as  clearly  expressed  in  functional  disease  as  it 
is  in  the  physiological  effects  of  stimuli.  The  pathological  dis- 
turbance of  function  is  purely  quantitative,  "nowhere  is  there  a 
qualitative  divergence."  The  function  exists  or  it  does  not  exist. 
If  it  is  present,  it  is  either  strengthened  or  weakened.  This  gives 
the  three  fundamental  forms  of  disturbance :  absence,  weakening 


12  IRRITABILITY 

and  strengthening  of  the  function.  No  function  other  than  the 
physiological,  even  under  the  greatest  pathological  alterations, 
exists  in  any  structure  of  the  body.  "The  muscle  does  not  per- 
ceive, the  nerve  moves  no  bone,  the  cartilage  does  not  think." 
In  this  way  Virchozu  rediscovered  in  the  domain  of  pathology 
the  law  that  his  great  teacher,  Johannes  Mitller,  had  already 
clearly  established  in  the  field  of  physiology.  But  this  law  can 
no  longer  be  applied  to  all  pathological  disturbances  of  the  nutri- 
tive and  formative  activities  of  the  cell.  Here  processes  occur 
which  do  not  consist  of  a  quantitative  change  of  the  normal 
phenomena,  but  in  the  appearance  of  wholly  foreign  states,  as 
in  the  case  of  amyloid  degeneration  or  heteroplastic  tumors. 
The  question  today  and  for  the  future  arises,  therefore,  as  to 
where  the  limits  of  the  validity  of  the  law  of  the  specific  energy 
of  living  substances  are  to  be  placed,  a  question  closely  con- 
nected with  the  other  before  mentioned,  of  the  relations  between 
functional  and  cytoplastic  metabolism. 

By  means  of  cell  pathology  Virchow  has  laid  the  foundations 
upon  which  our  modern  medical  attitude  is  built  and  which  must 
remain  essentially  forever  the  basis  of  all  future  medical  thought. 
Certain  critics,  lacking  in  appreciation  of  the  interrelations 
between  things  and  ignoring  the  safer  and  established  knowledge, 
have  considered,  in  view  of  the  unfoldings  of  the  researches  on 
immunity  and  of  serum  therapy,  that  the  time  of  cell-pathology 
was  passed  and  must  be  replaced  by  the  humoral-pathological 
teaching.  These  ultramodern  critics,  however,  have  here  com- 
pletely ignored  the  fact  that,  on  the  one  hand,  the  life  of  our 
body  is  built  up  from  the  life  of  all  of  the  contained  cells,  for 
life  in  our  body  exists  only  in  the  cells ;  and  on  the  other,  a  fact 
not  considered  by  them  is  that  the  components  of  the  body  fluids 
originate  from  vital  activity  of  the  cells  either  directly  or  indi- 
rectly. No  result,  indeed,  of  present  serology  can  alter  in  the 
least  degree  the  fact  that  every  disease  represents  only  a  disturb- 
ance of  the  physiological  processes  of  cell  life  of  the  organism 
and  the  harmony  in  their  combined  workings.  Indeed  the  more 
recent  observations  of  serology  and  chemotherapy  are  so  little 
opposed  to  cell-pathology  that  they  are  in  fact  only  possible  when 


THE  HISTORY  OF  THE  SUBJECT  13 

based  on  the  latter.  They  are  only  comprehensible  then  from 
the  unfoldings  of  cellular  pathology. 

Until  quite  recently  all  those  effects  of  external  factors  on  the 
living  substance  which  consist  in  excitation,  that  is,  in  an  increase 
of  their  specific  vital  processes,  have  always  stood  in  the  fore- 
ground of  all  researches  and  observations  on  irritability.  It  was 
gradually,  however,  more  and  more  recognized  that  the  depress- 
ing influence  of  stimuli  played  a  great  role  in  the  vital  process  of 
the  organism.  Brozvn  was  acquainted  with  exhaustion  produced 
by  stimuli,  and  the  discussion  of  ''asthenic"  diseases,  in  which  the 
irritability  was  reduced,  occupied  an  important  place  in  his  path- 
ology. That,  however,  in  the  normal  activities  of  the  organism 
such  depression  or  lessening  of  vital  manifestation  could  result 
from  the  influence  of  stimulation,  first  became  clear  after  the 
brothers  Weber'^  in  1846  discovered  the  inhibitory  effects  of  the 
galvanic  stimulation  of  the  vagus  upon  the  heart. 

Since  then  the  inhibitory  processes  in  nerves  have  been  fre- 
quently investigated  by  Schiff  (1823-1896),  Golts  (1834-1901) 
and  others,  who  gave  us  a  theory  concerning  the  same.  Only 
a  small  number  of  inhibitory  processes  were  known  at  that 
time,  as  for  instance  the  inhibition  of  the  croak  reflex  of  the 
frog,  or  the  inhibition  of  the  grasp  reflex  during  copulation 
of  these  animals  through  skin  stimuli,  and  a  few  other  cases. 
They  regarded  the  inhibitory  nervous  processes  as  a  special  state, 
of  which  the  inhibition  of  the  heart  through  the  vagus  was  the 
best  illustration.  Further,  the  Russian  physiologist  Sctscliowzv 
succeeded  by  directly  stimulating  certain  parts  of  the  central 
nervous  system,  especially  the  optic  lobes  of  the  frog,  in  producing 
inhibition.  It  was,  therefore,  frequently  assumed,  as  Sctscliowzv 
did,  that  in  the  brain  there  exist  special  inhibitory  centers,  just 
as  there  are  motor  centers.  This  view  was  later  shown  to  be 
untenable.  It  is  only  quite  recently,  and  especially  since  Sherring- 
ton has  shown  that  inhibition  plays  a  part  in  all  antagonistic 
muscle  movements,  that  we  have  obtained  a  broad  and  more 
thorough  understanding  of  the  inhibitory  processes  in  the  life 

1  Eduard  Weber:  "Muskelbewegung."  Article  in  Wagner's  Handwortcrbuch  der 
Physiologie,  Bd.   3.     Braunschweig  1846. 


14  IRRITABILITY 

of  the  organism,  and  a  physiological  explanation  of  this  important 
group  of  activities  of  the  central  nervous  system.  This  inhibitory 
effect  of  stimulation,  brought  about  by  the  involvement  of  the 
central  nervous  system  in  the  normal  organism,  was  studied  side 
by  side  with  the  depressing  effects  of  stimulation.  Claude  Ber- 
nard (1813-1878)^  first  discovered  that  the  excitation  of  all  living 
substance  could  be  depressed  or  totally  suspended  through  the 
influence  of  certain  anaesthetics,  such  as  ether  or  chloroform. 
By  a  series  of  experiments,  as  simple  as  they  were  convincing, 
the  French  scientist  showed  that  irritability  could  be  depressed 
in  mimosa  leaves,  the  growth  of  germinating  plant  seeds  and  the 
ferment  action  of  yeast  cells  stopped,  likewise  the  disintegration 
of  the  carbon  dioxide  in  the  cells  of  the  green  leaf,  as  well  as  the 
development  of  the  egg  cells,  and  also  the  movements  of  the 
animal  organism  and  the  sensations  of  man.  By  this  means  he 
recognized  that  not  only  does  all  living  protoplasm  possess  irri- 
tability, but  that  it  can  also  by  means  of  certain  substances  be  put 
into  the  condition  of  "anaesthesia,"  a  state  dependent  upon  a 
change  of  the  protoplasm,  which  he  termed  "semi-coagulation." 
Finally,  besides  the  more  apparent  processes  of  excitation  and 
those  less  so,  belonging  to  the  group  of  inhibition  and  depression, 
in  the  last  century  the  knowledge  of  the  subject  was  greatly  in- 
creased by  the  addition  of  another  group,  which  recently  in  con- 
sequence of  various  reasons  has  met  with  particular  interest.  These 
being  effects  of  stimuli  on  the  direction  of  movements  of  motile 
organisms,  it  became  more  and  more  recognized  that  these  curious 
manifestations  of  irritability,  which  appeared  to  have  such  a  sur- 
prising likeness  to  the  mysterious  attraction  and  repulsion  in  the 
sphere  of  electricity  and  magnetism,  occur  universally  in  the  vege- 
table as  well  as  in  the  animal  world.  These  movements  are  of 
the  greatest  biological  importance  for  the  obtaining  of  food, 
propagation,  protection  against  disease,  etc.  Botanists  have  long 
known  of  the  geotaxis  of  the  roots  and  stems  of  plants,  the 
heliotaxis  of  their  leaves  and  flowers  and  of  the  thigmotaxis 
of   their   tendrils.      Likewise   the   phototaxis    of    freely   moving 

1  Claude  Bernard:  "Lecons  sur  les  phenomenes  de  la  vie  communs  aux  animaux  et 
aux  vegetaux."     Paris  1878. 


THE  HISTORY  OF  THE  SUBJECT  15 

protistae  had  been  often  observed,  especially  by  Jihrctibcrcf  of 
Berlin,  well  known  for  his  researches  on  infusoria.  Then 
Engelmann,  Pfcffer,  Strassbunjcr,  Stalil,  and  many  others 
discovered  and  studied  more  carefully  the  facts  concerning 
chemotaxis,  thigmotaxis,  rheotaxis,  geotaxis,  phototaxis,  etc., 
of  bacteria,  motile  spores,  rhizopoda,  and  so  on.  The  question 
arose  if  one  should  regard  this  singular  behavior  of  the  unicellular 
organisms  as  an  expression  of  conscious  sensations,  discrimination 
or  will.  This  view  was  as  determinedly  denied  on  the  one  hand 
as  it  was  accepted  on  the  other.  Whilst  even  today  certain 
scientists  still  consider  the  reactions  of  the  unicellular  organisms 
as  a  manifestation  of  conscious  sensation,  discrimination  or 
will,  others  look  upon  them  as  unconscious  reflex  reactions  of 
cell  organism,  taking  place  as  purely  mechanically  as  the  si)inal 
cord  reflexes  of  vertebrates.  This  divergence  of  oi)inion  would 
have  practically  no  value  for  the  development  of  our  knowledge 
of  irritability  had  not  here,  as  in  the  case  of  the  relations  between 
the  mental  and  physical  processes  in  man,  the  view  been  enter- 
tained with  more  or  less  fervor,  that  at  some  stage  or  other  in 
the  chain  of  the  purely  physiological  processes  of  responsivity, 
an  intangible  factor  had  been  introduced  which  was  considered 
as  the  essential  ''cause"  of  the  peculiar  reactions  to  stimuli.  It 
is  not  here  the  place  to  enter  into  the  question  if,  and  in  what 
degree,  animal  psychology  may  be  a  field  of  scientific  research. 
Even  if  one  looks  upon  conscious  processes  as  effects  of  stimula- 
tion, in  both  lower  animals  and  in  man,  in  no  case  should  one 
assume  them  to  be  factors  of  an  essentially  different  nature, 
interrupting  the  chain  of  the  mechanical  reactions ;  neither  should 
one  consider  the  particular  characteristic  responses  observed  in 
unicellular  organisms  as  effects  of  non-mechanical  "causes."  As 
a  result,  a  mysticism,  in  reality  quite  foreign  to  it.  would  be  intro- 
duced into  physiology.  As  a  matter  of  fact  the  physiological 
investigations  for  the  tropic  reactions  of  stimuli,  which  have 
been  carried  out  in  great  number  since  the  end  of  the  eighties, 
have  shown  more  and  more  clearly  that  this  peculiar  behavior 
of  unicellular  organisms  towards  unilateral  stinnili  is  jiroduced 

1  Ehrenberg :  "Die  Infusionstiere  als  vollkommene  Organismcii."  Leipzig   1838. 


16  IRRITABILITY 

by  a  comparatively  simple  mechanism.  The  analysis  of  this 
shows  a  difference  in  the  intensity  of  the  exciting  or  depressing 
effect  produced  by  the  stimulus.  The  stimulus  exerts  its  influence 
unequally  upon  the  specific  activity  of  the  motor  elements  of 
different  parts  of  the  surface  of  the  cell  body.  This  dift'erence 
in  response  causes  the  axis  of  the  freely  moving  organism  to 
assume  a  different  direction  in  which  to  move.  It  is  compelled 
to  move  in  a  definite  direction  and  so,  in  this  field,  the  apparently 
mysterious  attraction  and  repulsion  of  living  organisms  toward 
stimuli  has,  by  means  of  the  most  simple  analysis,  been  robbed 
of  its  mystical  character. 

Finally,  I  should  like  to  touch  briefly  upon  a  view  of  the  irri- 
tability of  living  substance  which  has  recently  been  brought  for- 
ward by  Semon}  It  assumes  the  proportions  of  a  whole  system 
and  is  proclaimed  as  a  basis  for  the  comprehension  of  organic 
phenomena.  It  originated  with  an  idea  which  Hering^  developed 
many  years  ago  and  which  later  was  accepted  by  Haeckel,^ 
namely  that  heredity  is  a  species  of  memory  of  the  living  sub- 
stance. Semon  attributes  to  living  substance,  in  contrast  to  non- 
living, a  ''Mneme."  By  ''Mneme"  he  understands  the  capability 
of  living  substance  to  assume,  through  the  influence  of  a  stimulus, 
a  permanently  altered  condition.  The  latent  alteration  resulting 
from  the  stimulus  he  terms  "Engramm/'  These  '' Engramms" 
can  later,  however,  not  only  be  activated  by  the  reapplication  of 
the  original  stimulus,  but  also  by  other  stimuli,  so  that  the  state 
of  excitation  once  brought  about  by  the  original  stimulus  reap- 
pears. Semon  calls  the  reproduction  of  the  state  of  primary 
excitation  by  a  later  stimulus  "Ekphorie/'  A  great  number  of 
other  new  word  formations,  such  as  "chronogene  Engramme/' 
''phasogene  Ekphorie,"  ''mnemische  Homophonie/'  ''mnemisches 
Protomer"  and  countless  others  are  supposed  to  serve  for  the 
better  understanding  of  a  series  of  special  facts,  chiefly  in  the 

1  Semon:  "Die  Mneme  als  erhaltendes  Princip  im  Wechsel  des  organischen  Gesche- 
hens."     Zweite  verbesserte  Auflage,  Leipzig. 

2  Ewald  Hering:   "Uber   das   Gedachtniss  als   allgemeine    Function   der   organischen 
Materie."     Wein   1876. 

3  Ernst  Haeckel:    "Die    Perigenesis    der    Plastidule    oder    die    Wellenzeugung    der 
Lebenstheilchen."     Berlin  1876. 


THE  HISTORY  OF  TIIK  SUBJECT  1 


•V 


domain  of  the  processes  of  heredity.  Tliat  wliich  is  termed 
''Mneme'  and  " Engramm"  is  not  furtlier  analyzed.  Scmon 
expressly  declines  to  discuss  the  kind  of  alterations  in  which 
the  physical  or  chemical  nature  of  an  "lituiramm"  consists. 
Hence  physiological  analysis  has  not  been  advanced  in  any 
way  by  Scmon's  new  formation  of  words  api)lied  to  long- 
known  facts.  With  a  series  of  new  expressions  the  originator 
of  the  ''Mneme  doctrine"  deceives  himself,  as  well  as  a  number  of 
his  readers  not  endowed  with  the  critical  faculty,  into  supijosing 
that  he  has  achieved  a  serious  analysis.  Of  such,  however,  there 
is  not  a  trace.  As  can  be  conceived,  this  way  of  treating  the 
manifestations  of  life  has  met  with  no  further  attention  from  the 
physiological  side.  For  indeed,  what  physiologist  would  con- 
sider that  the  fact  of  muscle  responding  by  a  contraction  to  an 
induction  shock,  or  to  any  other  stimulus,  is  sufficiently  analyzed 
by  the  explanation  that  we  have  the  "Ekplioric"  of  a  state  of 
excitation  that  was  once  previously  produced  by  an  original 
stimulus  of  some  unknown  kind,  and  of  which  the  living  sub- 
stance of  the  muscle,  in  consequence  of  its  "Mucmc,"  has  retained 
a  latent  "Engramm^f  Here  the  deep  gulf  is  apparent  which 
exists  between  the  demands  of  a  physiological  analysis  and  the 
futile  explanation  of  the  mneme  doctrine.  Physiological  inves- 
tigation must  reject  such  a  manner  of  treating  its  problems. 

With  this  the  history  of  the  doctrine  of  irritability  enters  into 
its  present  phase  of  development.  To  future  research  remains 
then  the  problem  of  further  analyzing  irritability,  this  common 
property  of  living  substance,  and  finally  rendering  it  into  its  sim- 
plest chemical  and  physical  components.  This  last  goal  can  only 
be  approached  very  gradually,  step  by  step.  With  the  analysis  of 
irritability  we  shall  investigate  life  itself,  in  the  following  lec- 
tures it  will  be  my  endeavor  to  show  how  far,  with  our  present 
knowledge,  we  can  penetrate  by  this  path  into  the  great  secret. 


CHAPTER   II 


THE  NATURE  OF  STIMULATION 


Contents:  Principles  of  scientific  knowledge  and  research.  Origin  and 
meaning  of  the  conception  of  cause.  Cause  and  condition.  Criticism 
of  the  conception  of  cause.  The  conditional  point  of  view.  Con- 
ception of  cause.  The  conditional  point  of  view  applied  to  the  investi- 
gation of  life.  Conception  of  vital  conditions.  Definition  of  the 
conception  of  stimulation. 

The  common  problem  of  all  scientific  research  is  the  investi- 
gation and  formulation  of  natural  laws.  The  assumption  of  a 
unity  in  the  happenings  and  of  existence  in  the  world,  in  accord- 
ance with  definite  laws,  forms  the  indispensable  foundation  of  all 
scientific  study  and  is  fully  justified  by  experience.  Experience 
has  taught  us,  as  a  result  of  innumerable  individual  observations, 
the  existence  of  such  an  accordance,  whereas  in  not  a  single 
instance  has  it  been  shown  that  this  is  not  the  case.  We  are  thus 
justified  in  assuming  without  further  discussion  that  every  scien- 
tific research,  every  new  problem  which  we  approach,  is  likewise 
founded  on  this  unity  of  occurrences  in  accordance  with  natural 
laws.  Only  on  the  firm  basis  of  this  assumption  has  scientific 
investigation  a  purpose,  and  every  success  is  a  new  proof  of  this. 
There  is  an  unanimity  of  opinion  concerning  this  among  scientific 
investigators  in  all  fields. 

Not  such  complete  agreement,  however,  exists  in  regard  to  the 
question  by  what  symbols  of  human  thought  and  speech  these 
laws  can  be  described  in  part  as  well  as  in  toto,  so  that  existing 
laws  can  not  only  be  fully  and  conclusively  defined,  but  at  the 
same  time  without  the  use  of  superfluous  terms.  According  to 
Ernst  Mach,  thought  is  an  adaptation  to  facts.     Our  speech  is 


THE  NATURE  OF  STIMULATION  19 

simply  a  method  of  expression  of  our  thoughts  and  indeed  tlie 
most  satisfactory  form  we  have.  We  must,  tlierefore.  use  lliose 
symbols  which  are  most  closely  adajned  U)  facts  as  the  must 
precise  expression  of  these  existing  laws.  What  forms  of 
expression  have  we? 

It  might  appear  that  a  discussion  of  this  fundamental  cjuestion 
has  not  a  close  connection  with  our  special  subject  of  i)hysiol()gy 
of  stimulation.  This,  however,  is  not  the  case.  Indeed,  it  is  an 
irremissibly  previous  requirement  not  only  for  the  ehicidation, 
but  also  for  the  understanding  itself  in  this  particular  field.  We 
could  not  come  to  a  clear  understanding  in  this  field  without 
such  analysis.  The  interpretation  of  the  unity  of  ijeing  and  haj)- 
penings  in  accordance  with  natural  laws,  which  today  is  widely 
accepted  in  the  scientific  world  as  the  only  exact  one,  imi)lies  the 
assumption  of  a  ''causation"  according  to  which  things  are  ex- 
plained by  the  law  of  "cause"  and  "effect."  V  have  already  on 
various  occasions  taken  the  opportunity  to  criticise  this  view  and 
to  show  the  error  and  confusion  to  which  it  leads.  I  should  like 
here  to  enter  somewhat  more  in  detail  into  the  reason  for  this 
criticism.  It  is  particularly  directed  against  the  scientific  use  of 
the  term  "cause''  on  the  basis  of  our  best-known  theoretical  prin- 
ciples. It  is  clear  that  all  scientific  observations  and  explanations 
are  founded  on  experience.  Can  it  be  said  that  the  conception 
of  "cause"  originates  from  experience? 

We  can  say  with  absolute  certainty  that  the  conception  of 
cause  dates  from  prehistoric  times.  Its  beginning  reaches  back 
to  the  stone  age,  at  least  to  neolithic,  possibly  to  pakxolithic  cul- 
ture. This  is  demonstrated  by  the  careful  reconstruction  of  these 
prehistoric  races  based  on  a  critical  comparison  of  the  remains 
of  their  culture  with  that  of  primitive  races  living  today.  The 
ideas  of  these  primitive  races  show  an  inclination  to  an  cxtraor- 

1  Compare  with  this  Max  Verxvorn:  "Die  Entwickelutig  des  mcnschlichcn  Gcistcs." 
Jena,  Gustav  Fischer,    1910. 

Max  Verworn:  "Die  Erforschung  des  Lebens."  II  Auflage.  Jena,  Gustax'  Fischer, 
1911. 

The  same:  "Die  Fragen  nach  den  Grenzen  der  Erkenntniss."     Jena,  Gustav  Fischer, 

1908. 

The  same:  "Allgemeine  Physiologic."     V  Auflage.     Gustav  Fischer,  1909. 


20  IRRITABILITY 

dinary  degree  to  explain  all  happenings  in  the  world  anthropo- 
morphously.  All  happenings  in  surrounding  nature  are  given 
the  same  origin  as  the  activities  of  man  himself.  To  man,  on 
this  plane  of  phantastic  religious  speculation,  all  events  in  nature 
appear  as  acts  of  the  will  of  invisible  powers,  which,  having 
originally  proceeded  from  the  souls  of  dead  human  beings,  think, 
feel  and  act  exactly  as  he  does.  This  anthropomorphic  conception 
of  the  occurrences  in  the  surrounding  world  is  one  of  the  many 
conclusions  which  ensue  from  the  supposition  of  an  invisible 
soul,  which  can  be  separated  from  the  body.  It  was  this  con- 
ception which  gave  the  impetus  for  the  transition  of  human 
thought  from  the  era  of  the  naively  practical  to  the  era  of  the 
theoretical  spirit  in  that  far  removed  age.  In  this  anthropo- 
morphic transference  of  personal  subjective  impulses  of  will  to 
the  objectively  observed  events  of  the  surrounding  world,  lies 
the  origin  of  causal  conception,  which  since  then  has  been  gen- 
erally used  as  the  explanation  of  the  happenings  in  the  world. 
One  cannot  assert  that  the  formation  of  the  conception  of  cause  is 
purely  a  product  of  experience,  but  rather  a  result  of  naive  specu- 
lation. Even  if  a  later  evolution  of  human  thought  shows  a  con- 
tinued endeavor  to  dismantle  the  conception  of  cause  of  its  primi- 
tive trappings  and  to  modernize,  as  it  were,  its  outer  appearance, 
we  still  find  today  many  inner  components  clinging  to  it,  which 
do  not  agree  with  the  strict  demands  of  critical  scientific  exact- 
ness, demands  which  must  particularly  be  made  concerning  a 
conception  which  has  been  given  such  fundamental  importance 
in  theoretical  knowledge. 

I  wish  to  observe  here,  however,  that  the  conception  of  cause, 
even  though  more  or  less  unconsciously  so,  is  still  the  remains  of 
a  part  of  the  old  anthropomorphic  mysticism  carried  over  into 
our  own  times.  This  shows  itself  especially  in  the  conception 
of  force,  which  is  nothing  more  than  a  form  of  the  conception 
of  cause.  Force  is  the  cause  of  movement.  One  has  here  in 
anthropomorphic  manner  transferred  the  action  of  the  will  of 
man,  which  produces  movement  of  the  muscles,  into  lifeless 
nature.  The  force  of  the  sun  attracts  the  earth,  that  of  the  mag- 
net attracts  iron,  etc.     In  short,  one  has  introduced  a  mysterious 


THE  NATURE  OF  STIMULATION  21 

unknown  factor  instead  of  being  content  willi  the  sinii)Ic  descrip- 
tion of  facts,  such  as  Kirchhop  has  advanced  in  llie  field  of 
mechanics.  Although  of  late  natural  science  has  also  dispensed 
more  and  more  with  conception  of  force  as  a  means  of  explana- 
tion, it  is  still  today  not  wholly  done  away  with.  That  which 
applies  to  the  conception  of  force  is  likewise  true  of  the  concej>- 
tion  of  cause. 

Another  point  concerning  the  application  of  the  conception  of 
cause  seems  to  me,  however,  to  be  of  much  more  inii)ortancc, 
namely  that  a  single  cause  is  held  responsible  for  the  taking 
place  of  a  process.  One  endeavors  to  explain  a  process  in  gen- 
eral by  seeking  for  its  "cause."  The  cause  being  found,  the 
process  is  considered  as  fully  accounted  for.  This  idea  is  not 
only  widely  spread  in  everyday  life,  but  is  even  found  frequently 
in  natural  science,  especially  in  biology,  although  here,  it  should 
be  known,  the  processes  are  decidedly  more  complicated.  The 
search  for  the  "cause"  of  development,  for  the  "cause"  of  hered- 
ity, for  the  "cause"  of  death,  for  the  "cause"  of  the  respiration, 
for  the  "cause"  of  the  heart  beat,  for  the  "cause"  of  sleep,  for 
the  "cause"  of  disease,  etc.,  was  for  a  long  time  and  frequently 
even  today  a  characteristic  of  biological  investigation.  As  if 
such  a  complicated  process  as  development,  death  or  disease 
could  be  explained  by  a  single  factor!  In  reality,  one  has 
obtained  very  little  as  a  result  of  the  analysis  of  a  {process  by 
discovering  its  cause;  and  in  addition  the  false  impression  arises 
that  through  the  finding  of  this  one  factor  the  process  has  been 
definitely  explained.  It  has  been  generally  recognized  in  the 
natural  sciences  in  recent  times  that  no  process  in  the  w(^rld 
is  dependent  upon  one  single  factor  and  attempts  have  been  made 
to  give  this  fact  more  consideration. 

It  is  the  custom  at  the  present  time  to  hold  the  view  that  every 
process  or  state  is  brought  about  by  its  cause,  but  that  a  series  of 
conditions  are  also  necessary  to  the  production  of  the  ])rocess. 
Such  a  view,  however,  which  considers  that  two  ditTereiU  factors 
existing  at  the  same  time  are  necessary  to  the  acc(^mplishinent  <>f 

1  Gustav  Kirchhoff:  "Vorlesungen  iiber  mathematische  Physik.  Mcchanik."  LcipziK 
1876. 


22  IRRITABILITY 

every  happening  or  state,  namely,  the  cause  and  the  conditions, 
leads  to  new  difficulties,  for  then,  upon  a  more  exact  analysis 
arises  the  question :  Which  is  the  cause  and  what  are  the  condi- 
tions? It  is  very  soon  found,  however,  that  this  does  not  permit 
of  any  strict  differentiation,  as  the  two  conceptions  can  not  be 
sharply  separated.  This  difficulty  was  brought  to  my  notice  with 
particular  force  during  an  animated  discussion  with  a  friend 
and  colleague  about  twenty  years  ago,  which  I  have  always 
remembered.  I  had  observed  at  that  time  the  dependence  of 
pseudopod  formation  of  amoeboid  cells  on  the  oxygen  of  the 
medium,  and  had  found  that  the  expansion  phase  of  proto- 
plasmic movement,  that  is,  the  extension  of  pseudopods,  the 
centrifugal  flowing  of  the  protoplasm  into  the  surrounding 
medium  and  with  this  the  enlargement  of  the  surface  of  the  cell 
body,  only  takes  place  when  oxygen  is  contained  in  the  sur- 
rounding medium  and  never  occurs  in  its  absence.  Being  at  that 
time  wholly  under  the  influence  of  the  conception  of  cause,  I 
believed  that  oxygen  was  the  cause  of  the  formation  of  the 
pseudopods.  To  this  my  friend  made  the  objection:  "Yes,  I 
quite  acknowledge  the  fact  of  the  dependence  of  the  formation 
of  pseudopods  on  oxygen,  but  what  informs  me  that  the  oxygen 
is  really  the  cause?  It  might  be  simply  a  necessary  condition." 
This  objection  led  to  a  long  debate,  which  ended,  however,  with- 
out our  being  able  to  agree.  We  were  not  in  a  position  to  dis- 
tinguish between  the  conception  of  cause  and  that  of  condition, 
and  at  that  time  the  idea  did  not  occur  to  us  to  emancipate 
ourselves  from  the  conception  of  cause  deeply  implanted  in  us 
as  a  result  of  our  training.  In  fact,  one  is  greatly  embarrassed 
if  one  attempts  to  sharply  distinguish  by  a  definition  the  concep- 
tion of  cause  and  that  of  condition.  A  condition  is  a  factor  on 
which  a  state  or  a  process  is  dependent  for  its  existence  or  its 
taking  place.  To  the  conception  of  condition  belongs,  besides 
the  factor  of  relation,  that  of  necessity.  Every  condition  is  neces- 
sary to  the  existence  or  taking  place  of  this  state  or  process. 
Without  the  condition  in  question  the  state  or  process  does  not 
occur.  The  same  must  be  demanded  for  the  conception  of  cause. 
No  state  exists,  no  process  takes  place,  without  its  cause.     The 


THE  NATURE  OF  STIMULATION  23 

cause  then  has  itself  the  specific  character  of  a  condition,  it  is 
itself  a  condition.  Has  it  perhaps  then  some  specific  peculiarity 
in  contrast  to  the  other  conditions,  which  would  give  it  a  promi- 
nent place?  Experience  teaches  us  that  nothing,  that  is  to  say, 
no  state  or  process  in  the  world,  is  dependent  upon  a  single  factor 
alone.  There  are  always  numerous  factors  which  hring  about 
the  state  or  process.  Would  it  be  possible  to  distinguish  which 
of  these  particular  conditions  is  of  the  greatest  importance? 

First  of  all,  it  must  here  be  taken  into  consideration  that  the 
importance  of  a  condition  is  not  one  which  is  capable  of  increase 
or  decrease,  for  the  simple  reason  that  necessity,  which  forms 
an  essential  component  of  the  conception  of  cause  cannot  be 
varied.  A  factor  cannot  be  more  than  necessary  for  the  exist- 
ence of  a  state  or  the  taking  place  of  a  process.  If.  however, 
it  is  less  than  necessary,  then  it  is  not  necessary  at  all,  and 
the  state  or  process  exists  also  without  it,  that  is  to  say,  the 
factor  is  not  a  condition.  In  other  words :  all  conditions  for  a 
state  or  process  are  of  equal  value  for  its  existence,  as  tliex  are 
all  necessary. 

If  one  attempts  to  prove  by  means  of  concrete  exami)les  this 
statement  obtained  by  purely  logical  deduction — a  control  which, 
considering  the  experimental  nature  of  modern  thought,  never 
should  be  neglected  even  in  the  simplest  of  reasoning — it  might 
appear  that  an  objection  could  still  be  made  against  its  general 
validity.  From  various  instances  it  might  be  concluded  that 
there  are  conditions,  which  as  such  are  not  absolutely  necessary 
for  a  state  or  process,  but  can  be  replaced  by  other  factors.  .\n 
example  may  serve  to  make  this  clear.  I  pour  diluted  hydro- 
chloric acid  on  powdered  carbonate  of  sodium,  and  carbon  dioxide 
is  set  free.  The  addition  of  hydrochloric  acid  is  here  a  condition 
for  the  liberation  of  the  carbon  dioxide.  Without  the  presence  of 
the  hydrochloric  acid  the  process  does  not  occur.  Nevertheless 
I  can  substitute  diluted  sulphuric  acid  for  the  hydrochloric  acid. 
Here  it  would  appear  that  one  condition  can  be  replaced  by 
another.  But  one  must  not  be  deceived.  A  closer  observation 
soon  shows  that  the  process  has  not  been  sufficiently  analyzed 
if  we  look  upon  the  addition  of  hydrochloric  acid  as  a  condition 


24  IRRITABILITY 

for  the  liberation  of  carbon  dioxide.  It  is  not  the  presence  of 
hydrochloric  acid  or  sulphuric  acid,  as  such,  which  is  a  condition 
for  the  process,  but  rather  the  separation  of  the  sodium  atoms 
from  their  combinations  with  the  oxygen  in  the  molecule  of  the 
carbonate.  This  reaction  can  occur  as  a  partial  component  in 
very  different  complexes  of  processes.  Or  to  quote  another 
example,  taken  from  the  subject  with  which  we  are  especially  here 
concerned.  I  allow  an  induction  shock  to  act  on  the  nerve  of 
a  nerve  muscle  preparation  of  the  frog.  The  muscle  con- 
tracts. The  electric  stimulus  is  the  condition  for  the  muscle  con- 
traction. But  I  can  substitute  for  the  induction  shock  a  mechani- 
cal stimulus  by  sudden  pressure  of  the  nerve.  The  muscle  again 
contracts.  The  analysis  again  shows  that  the  induction  shock  as 
such  was  not  the  condition  for  the  muscle  contraction,  but  the 
excitation  of  the  nerve  which  it  produced  and  which  is  conducted 
as  a  specific  impulse  to  the  muscle.  This  excitation  of  the  nerve 
can,  however,  be  induced  by  very  different  kinds  of  processes, 
namely,  by  all  processes  which  possess  in  common  the  condition 
that  they  suddenly  increase  certain  disintegration  processes  in  the 
living  nerve  substance.  Indeed,  the  further  analysis  of  the  whole 
process  shows  in  addition  that  the  nerve  impulse  as  such  likewise 
does  not  form  a  condition  for  the  contraction  of  the  muscle,  but 
it  first  of  all  produces  the  necessary  condition  for  the  muscle 
contraction  by  suddenly  greatly  increasing  certain  chemical  pro- 
cesses, which  take  place  in  the  living  substance  of  the  resting 
muscle.  The  nerve  impulse  can,  therefore,  also  be  replaced  by 
other  processes,  if  only  these  contain  the  condition  for  an  increase 
of  disintegration  of  the  muscle  substance,  as  in  the  case  of  the 
direct  stimulation  of  the  curarized  muscle,  where  the  influence 
of  nervous  impulses  is  totally  eliminated.  In  a  further  analysis 
of  this  process  we  should  penetrate  even  more  deeply  into  the 
differentiation  of  the  individual  constituent  processes  and  the 
isolating  of  the  special  conditions  on  which  each  link  in  the  chain 
is  dependent. 

Such  an  analysis  then  shows  us  the  following:  Every  thing, 
every  state  or  process,  is  a  complex  of  numerous  components,  of 
which  one  always  conditions  the  other  in  the  manner  that  the 


***^a 


■»*«; 


THE  NATURE  OF  STIMULATKJN  25 

individual  conditioning  components  are  themselves  in  their  turn 
contained  as  constituents  of  other  complexes  and  are  condi- 
tioned here  again  by  other  factors.  These  factors  in  themselves 
as  such  are  not  directly  necessary  to  the  taking  place  or  existing 
of  the  special  component  and  can,  therefore,  be  replaced  by 
others.  Closer  observation  shows  that  there  is  a  constant  inter- 
dependence between  all  things  in  the  world.  Ei'cr\  thing  in  the 
world  is  indirectly  dependent  ui)on  every  other,  altliougli  often  so 
remotely  that  we  are  not  able  to  trace  the  connection.  Abs(jlute 
things,  completely  isolated  and  independent  of  others,  do  not  exist 
in  the  world.  In  observing  and  studying  complexes  individually, 
we  must  not  forget  that  we  only  think  of  them  as  isolated  from 
the  great  eternal  coherence,  from  which  they  are  in  reality  not 
separated.  The  conception  of  condition,  however,  only  then  has 
meaning,  if  we  refer  to  it  in  connection  with  the  direct  depenci- 
ence  of  one  factor  upon  another.  Nevertheless  if  we  understand 
by.  conditions  those  which  are  connected  by  multitudinous  inter- 
mediate components,  then  we  would  render  the  conception  of 
conditions  useless.  For  if  every  thing  in  the  world  were  the 
condition  for  every  other,  the  conception  of  relation  would  lose 
its  value  in  special  states  or  processes.  Should  the  conception  of 
condition  have  a  meaning  in  regard  to  a  certain  state  or  process, 
then  we  should  only  look  upon  that  part  of  a  complex  upon  which 
the  other  is  directly  dependent  as  a  condition.  When,  however, 
we  meet  with  a  factor  for  a  process  or  state,  which  can  ai)par- 
ently  be  replaced  by  another  factor,  we  have  not  carried  the 
analysis  far  enough.  Upon  deeper  penetration  into  the  subject, 
it  is  found  that  the  essential  condition  for  the  process,  which 
exists,  is  a  component  common  to  both  factors,  one  of  which  in 
consequence  can  replace  the  other. 

It  is  the  task  of  all  scientific  research  to  penetrate  deeper  and 
deeper  into  these  relations,  these  connections  and  the  order  of 
succession  of  states  and  processes  and  to  separate  them  into 
their  individual  components,  and  in  this  way  gain  a  more  thor- 
ough knowledge  of  the  constancy  of  existence  and  happenings  in 
the  world. 

This  analytical  process,  it  is  true,  only  advances  very  grad- 


26  IRRITABILITY 

ually,  and  we  must  accept  for  the  present,  especially  in  the  com- 
plex biological  processes,  that  a  whole  complexity  of  members 
appear  conditioned,  and  that  a  complex  aggregate  is  a  con- 
dition of  the  whole  process.  We  are  not  yet  in  the  position  to 
define  the  special  components  of  the  constituent  processes.  It 
is  only  step  by  step  that  we  are  able  to  differentiate  the  necessary 
from  the  accessory  parts  in  these  complexes.  However,  we  are 
here  only  concerned  for  the  present  with  a  purely  theoretical 
question  and  we  may  be  permitted  to  say:  If  we  maintain  that 
the  conception  of  condition  has  as  an  integral  part  the  element 
of  necessity  and  of  relation  to  a  special  thing,  then  there  are  no 
substituting  conditions.  For  then  every  condition  for  a  state  or 
process  is  of  equal  value.  There  is  no  justification  t<3  give  more 
prominence  to  one  condition  and  place  it  in  the  position  of  being 
the  "cause/' 

If  the  cause  is  elevated,  then  it  is  done  from  some  superficial 
motive.  This  is  confirmed  by  a  glance  at  the  practical  use  of  the 
term  cause.  The  cases  in  which  the  cause  is  always  at  once 
clearly  recognized  and  named  without  doubt  or  hesitation  are 
those  where  a  new  factor  is  added  to  an  already  existing  system 
of  conditions,  which  bring  about  a  process.  When  such  a  process 
is  produced,  the  last  added  condition  is  considered  as  "cause." 
A  shock  acts  on  an  explosive  body,  the  body  explodes :  the  shock 
is  considered  the  cause.  An  induction  shock  acts  on  a  muscle,  the 
muscle  contracts ;  the  induction  shock  is  looked  upon  as  the  cause 
of  the  muscle  contraction.  To  regard  only  the  last  added  con- 
dition as  being  of  especial  importance  to  the  taking  place  and  the 
explanation  for  a  process  is,  however,  a  standpoint  which  could 
satisfy  only  the  most  superficial  of  observers. 

In  a  scientific  investigation  such  methods  should  play  no  role. 
For  to  every  careful  observer  it  must  appear  quite  clear  from  the 
beginning,  that  the  previously  existing  conditions  have  as  great 
a  value  for  the  taking  place  of  the  process  and  its  explanation  as 
that  last  added. 

The  induction  shock  would  not  have  produced  the  charac- 
teristic effect  had  not  the  other  conditions  been  already  previously 
combined,  had  not  certain  special  atoms  in  the  molecule  of  the 


THE  NATURE  OF  STIMULATION  27 

explosive  combination  in  consequence  of  former  processes 
assumed  quite  a  peculiar  labile  position,  had  not  in  the  evolution 
of  the  muscle  in  the  growth  and  metabolism  certain  combinations 
been  formed,  and  certain  chemical  processes  taken  place. 

Therefore  if  I  do  not  analyze  these  previously  existing  pro- 
cesses and  the  conditions  brought  about  by  them  in  the  system 
of  the  explosive  substances  or  the  muscle,  and  simj)ly  know  the 
condition  added  last,  then  I  have  learned  nothing  of  the  process 
itself,  have  explained  nothing.  The  time  of  a])plication  of  a  new 
condition  does  not  justify  in  any  degree  the  assignment  of  a  domi- 
nant position  to  a  factor.  But  more :  in  many  cases  there  is  not 
a  question  at  all  of  the  addition  of  a  process  to  an  existing  state, 
but  rather  of  the  simultaneous  interference  of  two  or  more  pro- 
cesses. Several  conditions  can  appear  at  the  same  time.  In  other 
cases  the  sequence  of  the  combination  can  be  reversed.  Which 
then  is  the  cause?  Has  the  process  several  causes,  or  has  it  no 
cause?  Here  one  sees  plainly  to  what  absurd  results  it  leads  if 
time  alone  is  used  as  a  basis  of  the  conception  of  cause.  To 
illustrate  this  I  return  to  the  case  of  the  liberation  of  carbon 
dioxide  from  carbonate  of  sodium.  I  place  anhydrous  carbonate 
of  sodium  in  a  beaker  and  add  hydrochloric  acid.  The  carbon 
dioxide  escapes.  Here  the  addition  of  hydrochloric  acid  would 
be  assumed  to  be  the  cause  of  the  freeing  of  the  gas.  Then  I  put 
hydrochloric  acid  in  a  beaker  and  add  carbonate  of  sodium.  The 
same  process  takes  place,  but  now  the  addition  of  carbonate  of 
sodium  would  be  considered  the  cause  for  the  formation  of  gas. 
Now  I  put  both  simultaneously  into  a  beaker.  Again  the  same 
process.  Which  was  now  the  cause?  Has  the  process  now  tzco 
or  has  it  no  cause  at  all?  Finally  I  put  anhydrous  carbonate  of 
sodium  and  hydrochloric  acid  in  ether  solution  into  the  beaker. 
The  formation  of  gas  does  not  take  place,  and  yet  both  causes  for 
this  formation  of  gas  are  present,  the  carbonate  of  sodium  and  the 
hydrochloric  acid.  Only  when  I  add  water  to  the  mixture  does  tlie 
formation  of  carbon  dioxide  take  place.  Here  water  would  be 
considered  the  cause.  Hence  every  condition  would  be  in  suc- 
cession the  cause  for  one  and  the  same  process.  Under  some 
circumstances  the  same  process  would  have  scleral  and  in  others 


28  IRRITABILITY 

no  cause  at  all.  It  is  scarcely  necessary  for  further  comments 
upon  the  value  of  the  conception  of  cause  for  the  scientific  expla- 
nation of  a  state  or  process.  If  we  do  not  seek  to  introduce 
into  exact  science  the  antiquated  symbols  which  have  become  use- 
less and  belong  to  a  primitive  phase  of  development  of  human 
thought,  there  cannot  be  a  moment's  doubt  that  a  strict  scientific 
analysis  in  whatever  field  of  investigation  it  may  be  carried  on  can 
consist  only  in  the  study  of  all  the  conditions  concerned  in  a  state 
or  process.  If  this  is  done,  then  the  work  of  exact  research  is 
accomplished.  Further  problems  do  not  exist.  The  use  of  super- 
fluous terms  or  symbols  for  the  definition  of  things  would  be  in 
opposition  to  the  fundamental  principle,  already  brought  forward 
by  Kirchhoff,  especially  for  mechanics,  namely,  that  of  formulat- 
ing comprehensively  and  in  the  simplest  manner  the  processes 
which  take  place  in  nature. 

At  first  glance  one  might  be  tempted  to  find  an  incompleteness 
in  the  observation  and  description,  when  a  conditional  standpoint 
is  adopted.  It  might  be  thought  that  conditionalism  were  a 
purely  formal  method  of  observation,  and  only  considered  the 
interdependence  of  things,  but  not  the  properties,  the  nature  of 
the  objects  themselves.  Regarded  more  closely,  however,  it  is 
seen  that  this  objection  does  not  hold  good.  For  what  is  a 
condition  ? 

A  condition  is  in  itself  a  thing  of  quite  distinct  properties. 
The  properties  of  a  thing  are,  however,  determined  by  the  specific 
combination  of  conditions  which  characterize  the  thing.  The 
conditions  by  which  a  thing,  that  is  to  say,  a  state  or  process,  is 
determined,  are  identical  with  its  being  and  nature;  in  other 
words,  they  are  the  thing  itself.  Purely  formal  relations  without 
essence  would  be  altogether  an  absurd  fiction  not  in  accord  with 
reality,  and  which  even  the  science  of  mathematics  does  not 
acknowledge,  for  we  cannot  have  a  conception  without  concrete 
content,  just  as  in  nature  we  do  not  find  a  form  existing  inde- 
pendently of  a  thing.  Every  thing  is  equal  to  the  sum  of  all  its 
conditions  and  depending  upon  the  uniform  constancy  in  accord- 
ance with  natural  laws  is  solely  determined  by   its  conditions. 


THE  NATURE  OF  STIMULATION  29 

The  problem  of  all  scientific  research  consists  wholly  in  the 
ascertaining  of  the  conditional  interdependcncy. 

A  state  or  process  is  solely  determined  by  the  sum  total  of  its 
conditions.  A  state  or  process  is  identical  zvith  all  of  its  condi- 
tions in  totality.  From  this  it  follows  that  c(jual  states  or  pro- 
cesses are  always  the  expression  of  cfiual  conditions  and  wherc- 
ever  unequal  conditions  exist,  une(iual  states  or  processes  will 
result ;  and  further,  a  state  or  process  is  completely  investigated 
when  the  entire  number  of  its  conditions  is  ascertained. 

This  fundamental  statement  of  conditionism  should  be  en- 
graved over  the  portals  to  the  entrance  of  every  scientific  inves- 
tigation. 

That  there  is  not  the  least  difficulty  in  presenting  scientific 
observations  strictly  according  to  these  principles  of  conditionism. 
and  that  one  can  perfectly  well  do  without  the  causal  conception 
in  a  scientific  description,  I  have  shown  by  a  concrete  example, 
namely,  in  the  fifth  edition  of  my  "General  Physiology."  In  the 
whole  volume  the  conception  of  cause  is  only  mentioned  in  one 
place,  where  its  theoretical  value  is  criticised,  elsewhere  not  at 
all,  and  yet  I  do  not  think  that  any  one  will  miss  this  conception, 
and  indeed,  if  their  attention  is  not  especially  called  to  the  fact, 
even  notice  the  omission. 

These  principles  of  an  exact  conditional  investigation  must  also 
guide  us  in  the  analysis  of  the  processes  of  stimulation.  The 
process  of  stimulation  is  especially  apt  to  tempt  one  to  emi)loy 
the  old  conception  of  cause,  for  it  belongs  to  that  group  of  pro- 
cesses which  originate  from  an  already  existing  system  by  the 
addition  of  a  new  factor.  An  electric  stimulus  acts  on  the  muscle. 
The  muscle  contracts.  The  stimulus  is  considered  the  cause  of 
the  contraction.  But  wdiat  would  I  explain  if  I  were  to  prove 
that  the  stimulation  is  the  cause  of  the  contraction? 

The  history  of  physiology  shows  us  that  this  subject  has  ad- 
vanced long  since  far  beyond  the  stage  of  being  satisfied  with 
such  an  explanation.  Today  the  process  would  only  then  be 
fully  investigated  if  we  knew  the  entire  number  of  its  conditions 
and  had  traced  the  dependency  of  the  individual  partial  con- 
stituents of  the  wdiole  complex  process  ui)on  one  aiK^thcr.     For 


30  IRRITABILITY 

this,  however,  it  is  essential  that  we  study  the  conditions  already 
existent  in  the  entire  system  previous  to  the  action  of  the 
stimulus. 

That  which  we  describe  with  the  word  life  is  an  exceedingly 
complex  process.  If  we  analyze  life,  it  is  found  to  be  composed 
of  an  immense  number  of  separate  constituent  processes,  each 
one  being  conditioned  by  the  others.  These  constituent  pro- 
cesses are  the  vital  conditions.  A  vital  process  occurs,  and  must 
occur,  where  and  when  the  whole  sum  of  vital  conditions  is 
realized.  It  is  identical  with  the  sum  total  of  the  vital  condi- 
tions. If  only  one  condition  is  absent,  then  life  does  not  exist. 
It  is  then  expedient  to  reserve  the  expression  ''life"  for  the 
entire  sum  of  the  vital  conditions.  When  we  speak  of  the  indi- 
vidual constituent  processes  as  "vital  processes"  in  the  plural, 
we  must  bear  in  mind  that  in  reality  each  is  not  in  itself  life. 
Only  the  whole  complex  "lives,"  not  an  individual  constituent 
of  the  same.  Living  substance  is  rather  the  whole  system,  and 
not  a  constituent  part  of  the  same,  not  a  piece  of  protoplasm,  not 
a  nucleus  and  not  a  specific  protein  combination  in  the  cell. 

A  property  of  this  system  should  receive  our  consideration  at 
this  point.  It  is  a  characteristic  of  every  system  in  the  world, 
namely,  the  fact  that  a  system  is  not  isolated  from  its  surround- 
ings. It  is  a  deception  resulting  from  the  selective  action  of  our 
sensory  organs,  if  we  consider  the  bodies  as  separated  and  iso- 
lated from  their  environment.  This  deception  disappears  upon 
further  analysis  and  when  we  assist  our  organs  of  sense,  which 
only  respond  to  certain  parts  of  the  whole  process,  by  experi- 
mental methods  of  investigation.  Our  experience  then  shows 
us  that  an  isolated  system  does  not  exist,  but  that  there  are 
instead  everywhere  connections  which  extend  further  and  fur- 
ther into  the  infinity  of  the  world.  An  organism  is  consequently 
no  deliminated  system  and  the  vital  process  cannot,  therefore,  be 
sharply  separated  from  the  processes  in  the  medium.  We  can- 
not draw  a  sharp  line  between  vital  processes  and  say:  on  the 
right  we  have  factors  which  are  necessary  for  the  maintenance 
of  life,  and  on  the  left  factors  which  are  not  necessary.  The 
conditional  connection  between  individual  processes  extends  to 


THE  NATURE  OF  STIMULATION  31 

the  entire  world,  and  likewise  a  great  series  of  constituents,  each 
influencing  the  others,  extend  from  the  medium  into  the  organism. 
The  nature  of  our  sense  perception,  and  consequently  the  knowl- 
edge derived  therefrom,  is  such  that  we  are  obliged  to  arbitrarily 
take  into  consideration  merely  fragments  from  the  endless  inter- 
dependence of  all  things  in  the  world,  and  so  we  separate  the 
vital  conditions  of  the  organisms  from  their  surrounding  factors, 
as  though  they  were  independent.  A  conscientious  theoretical 
analysis  requires  that  we  should  never  forget  that  in  reality  such 
an  isolation  does  not  exist.  Only  with  the  recognition  of  this 
can  we  distinguish  for  practical  purposes  between  internal  and 
external  vital  conditions.  In  such  a  differentiation  the  internal 
vital  conditions  which  compose  the  living  system  conceived  to  be 
isolated,  are  the  organs,  the  tissues,  the  cells,  the  protoplasm  and 
the  cell  nucleus,  and  within  the  protoplasm  and  the  nucleus  the 
arrangement  and  quantitative  relations  of  certain  substances, 
such  as  proteins,  salts,  water  and  the  thousands  of  special  com- 
ponents with  their  interactions  and  continued  alterations.  On 
the  other  hand,  the  external  vital  conditions,  which  act  on  the 
periphery,  are  the  conditions  of  the  surrounding  medium,  as 
foodstuffs,  water,  oxygen,  static  and  osmotic  pressure,  tempera- 
ture, light,  etc.  But  this  distinction  has  only  a  practical  value 
for  the  study  of  the  organism  as  an  independent  system.  Theo- 
retically it  is  as  impossible  to  make  a  sharp  distinction  between 
internal  and  external  vital  conditions,  as  to  distinguish  between 
the  vital  conditions  generally  and  the  more  remote  conditions  of 
the  environment.  All  these  conditions  form  a  widely  branching 
system  of  factors  of  which  one  is  conditioned  by  the  other  reach- 
ing continually  from  the  interior  of  the  vital  system  into  the 
surrounding  medium,  so  that  on  the  periphery  of  the  system  it 
cannot  always  be  said  whether  or  not  a  component  still  belongs 
to  life.  Considering  these  circumstances  we  can  rouglily  for  the 
present  define  the  conception  of  stimulus  as  follows : 

A  stimulus  is  every  change  in  the  zntal  conditions. 

The  most  essential  point  in  this  definition  is  the  relaticMi  of 
the  conception  of  stimulus  to  that  of  vital  conditions.  These 
relations,  however,  call  for  a  brief  exi)lanation.     Here  again  the 


32  IRRITABILITY 

conditional  method  of  observation  saves  us  from  error,  for  it 
v^ould  be  wrong  to  place  the  conception  of  stimulus  and  vital 
conditions  in  contrast  to  one  another,  one  excluding  the  other. 
On  the  other  hand,  this  method  of  observation  shows  that  the 
stimuli  are  likewise  only  conditions,  but  conditions  producing 
certain  changes  in  the  vital  system.  If  a  stimulus  acts,  that  is, 
if  there  is  any  change  whatever  in  the  vital  conditions,  the  whole 
complex  of  life  in  consequence  of  the  dependency  of  the  con- 
stituent parts  upon  each  other  is  also  changed,  and  a  new  state 
of  living  substance  occurs.  Stimuli  are,  therefore,  also  only 
vital  conditions,  but  vital  conditions  for  new  vital  manifestations. 
The  relation  of  one  given  state  to  another,  forms  an  indispensable 
point  in  the  understanding  of  vital  conditions  as  well  as  that  of 
the  stimulus.  The  stimulus  becomes  a  vital  condition  for  the 
new  state  which  it  produces.  It  is  only  a  stimulus  relatively  to 
the  original  state,  which  previously  existed.  The  essential  point, 
therefore,  in  the  conception  of  the  stimulus  is  that  of  alteration. 
An  example  will  serve  to  make  this  clearer.  If  Amoeba  Umax  are 
bred  in  a  hay  infusion  they  appear  in  countless  masses.  Observed 
in  water  in  a  watch  glass  they  show  at  first  the  well-known  form 
of  Amoeba  proteus  with  short,  broad,  lobate  pseudopods.  (Figure 
1,  A.)  After  a  period  of  rest,  however,  they  gradually  assume  the 
characteristic  elongated  Umax  form.  (Figure  1,  B.)  In  this  shape 
they  constantly  move  about.  But  if  I  add  to  the  water  only  a 
faint  trace  of  diluted  solution  of  caustic  potash,  the  amoebae  first 
assume  the  shape  of  a  ball  (Figure  1,  C),  and  then  after  a  time, 
stretch  out  long,  pointed  pseudopods,  which  give  them  the  charac- 
teristic form  of  Amoeba  radiosa.  (Figure  1,  D  and  E.)  They 
remain  permanently^  in  this  form.  I  have  observed  them  for  sev- 
eral hours  at  a  time.  They  move  in  the  same  manner  as  Amoeba 
radiosa.  They  draw  in  one  pseudopod,  stretch  out  another  and 
float  freely  in  the  water  in  contrast  to  their  Umax  state,  in  which 
they  are  always  attached  to  some  support.  The  long,  pointed, 
often  threadlike  pseudopods,  yield  to  every  movement  of  the 
water,  bending  in  consequence  like  whipcords.     In  this  example 

1  Max     Verworn:    "Die    polare     Erregung    der     lebendigen     Substanz     durch     den 
galvanischen  Strom."     In  Pfliigers  Archiv  f.  d.  ges.  Physiologie  Bd.  65,   1896. 


Fig.  1. 


34  IRRITABILITY 

the  amoebse  under  the  vital  conditions  existing  in  tap  water  have 
Umax  form.  The  vital  conditions  undergo  a  change  by  the  addi- 
tion of  a  solution  of  caustic  potash,  which  acts  as  a  stimulus.  The 
consequence  is  a  reaction,  in  which  the  animal  assumes  radiosa 
form.  By  the  action  of  the  stimulus  a  new  state  of  the  living 
substance  is  produced,  and  remains  as  long  as  the  solution  of 
caustic  potash  is  contained  in  the  medium.  The  solution  of 
caustic  potash  is,  therefore,  a  stimulus  for  the  state  of  the  vital 
system,  which  is  manifested  in  the  Umax  form,  whilst  for  the 
state  of  the  system  which  shows  itself  in  the  radiosa  form,  it  is  a 
vital  condition.  If  I  place  the  amoebae  of  the  radiosa  form  once 
again  in  tap  water,  they  assume  the  proteus  and  then  the  Umax 
form.  The  withdrawal  of  the  solution  of  caustic  potash,  the  pres- 
ence of  which  is  a  vital  condition  for  the  radiosa  state,  acts  as  a 
stimulus,  which  results  in  a  transition  of  the  vital  system  to 
another  state.  By  altering  the  medium  I  can  at  will  bring  about 
this  change  of  form  in  the  same  individuals.  In  this  way  one  and 
the  same  factor  can  figure  as  stimulus  and  vital  condition,  accord- 
ing to  the  state  of  the  vital  system  on  which  it  acts.  Whilst  its 
addition  acts  as  stimulus  in  the  one  state,  its  withdrawal  acts  as  a 
stimulus  in  the  other  state,  which  it  has  produced.  The  same 
fact  is  shown  by  the  well-known  example  of  Artemia  salina,  which 
on  being  placed  in  fresh  water  changes  into  Branchipus  stagnalis 
and,  when  again  introduced  into  sea  water,  becomes  once  more 
Artemia  salina. 

These  facts  show  clearly  that  some  stimuli  can  also  be  con- 
sidered as  vital  conditions.  In  the  absence  of  certain  stimuli, 
life  could  not  exist  for  any  length  of  time.  Iil  the  highly  dif- 
ferentiated cell  community  of  the  animal  organism,  for  instance, 
as  a  result  of  the  coexistence  of  the  cells  and  the  tissues,  many 
parts  have  forfeited  in  a  measure  their  independence.  An 
example  of  this  is  the  skeletal  muscle,  which,  in  the  absence  of 
impulses  from  the  nervous  system,  reaches  a  low  level  of  chemi- 
cal change  and  energy  transformation.  Here  the  nervous  impulses 
which  act  as  momentary  stimuli,  are  also  in  the  course  of  time 
indispensable  vital  conditions.  Without  them  the  muscle  would 
gradually  become  atrophied  from  inactivity.     The  same  applies 


THE  NATURE  OF  STIMULATION  35 

to  all  other  tissues  of  our  bodies.  The  functional  stimuli  are  for 
them  at  the  same  time  vital  conditions.  These  vital  conditions 
undergo  fluctuations  and  interruptions  but  at  each  alteration 
from  a  given  state  they  act  as  stimuli. 

Stimulus  is  every  change  in  the  vital  conditions.  But  is  this 
definition  complete?  Are  we  really  justified  in  regarding  every 
alteration  in  the  vital  conditions  as  a  stimulus? 

In  considering  this  question,  one  point  nui>t  not  be  omitted. 
This  is  the  fact  that  one  of  the  chief  characteristics  of  the  vital 
process  is,  that  it  undergoes  continuous  change.  A  vital  process 
involves  not  simply  an  alteration  in  metabolism  or  transformation 
of  energy  in  the  sense  that  the  same  chemical  processes  con- 
tinuously reoccur  in  the  same  manner.  Such  a  view  could  only 
be  admissible  for  the  observation  of  living  substance  during  a 
limited  period.  An  investigation  over  a  long  period  of  time 
shows  rather  that  every  living  system  alters  as  long  as  it  exists, 
although  this  alteration  is  very  gradual.  The  constituent  pro- 
cesses, in  short,  continuously  undergo  metabolic  change  both 
quantitative  and  qualitative  in  nature. 

If  we  observe  the  occurrences  in  a  living  system  at  various 
moments  of  the  cycle  of  life,  we  will  find  that  the  condition 
differs  qualitatively  at  each  period.  The  progressive  alteration 
of  the  system  is  such  that  every  state  of  living  substance  condi- 
tions another,  by  which  it  is  followed.  No  state  can  perma- 
nently exist  as  such.  Every  state  is  the  product  of  the  pre- 
ceding, as  it  in  turn  conditions  its  successor.  Consequently  the 
relations  of  the  system  to  the  surrounding  medium  also  undergc* 
alteration,  even  when  the  external  factors  themselves  in  no 
way  alter.  That  which  today  is  still  a  vital  condition,  is  not 
in  consequence  necessarily  one  tomorrow.  Those  progressive 
changes  exist  continuously  until  the  death  of  the  system  takes 
place.  They  characterize  life.  It  is  development,  and  life 
cannot  exist  without  development.  Death  is  only  the  la>t  phase 
of  development.  The  individual  constituent  processes  of  metab- 
olism gradually  change  to  such  a  degree  that  they  can  no  longer 
work  harmoniously  together.  Then  the  cliain  of  processes  is 
interrupted  at  one  point  or  another.     The  system  develops  into 


36  IRRITABILITY 

death  or,  on  the  other  hand — and  this,  as  Weissman  especially 
emphasizes,  is  realized  in  the  case  of  unicellular  organisms — a 
corrective  process  takes  place,  a  process  of  cell  division  by  which 
the  original  state  of  the  cell  is  restored  and  development  begins 
anew  and  in  a  similar  manner. 

Ought  we  to  designate  these  constant  alterations  in  the  inner 
vital  conditions  as  "stimuli"?  Usage  in  this  connection  has 
already  answered  in  the  negative,  by  applying  to  them  the  word 
"development/'  And  this  use  is  in  a  certain  sense  justified. 
Let  us  imagine  an  organism  or  any  other  object  for  the  purpose 
of  investigation  as  isolated  from  its  surroundings.  This  con- 
ception, which  we  have  already  stated,  proves  untenable  on  closer 
analysis,  but  it,  however,  is  based  on  the  nature  of  the  meth- 
ods of  human  observation  and  is  indispensable  for  practical  use 
within  certain  limits.  Then  the  inner  vital  conditions  belong  to 
the  organism,  the  external  to  the  medium.  They  differ  in  so  far 
that  the  external  vital  conditions  can  exist  permanently  without 
alteration,  that  is,  independently  of  the  development  of  living 
systems,  whilst  the  inner  vital  conditions  of  every  living  organism 
continuously  and  progressively  undergo  alteration.  In  this  sense, 
but  only  in  this,  there  is  evidently  a  difference  between  the  inner 
and  outer  vital  conditions,  which  permits  a  separation  of  the  two 
groups.  But  we  should  always  bear  in  mind  that  this  separation 
cannot  be  sharply  defined.  On  the  same  basis  we  assume  that 
the  organism  for  purposes  of  study  is  separated  from  its  sur- 
roundings as  an  independent  system,  which  leads  us  in  conse- 
quence to  contrast  the  alterations  in  the  internal  with  those  in 
the  external  vital  conditions,  in  which  we  designate  the  first  as 
processes  of  development,  the  latter  as  stimuli.  This  distinction, 
as  all  differentiations  and  separations  in  nature,  gives  us  only  a 
practical  working  basis. 

In  this  way  we  confine  the  conception  of  the  stimulus  to  all 
alterations  in  the  external  vital  conditions  of  a  living  system, 
considered  as  isolated.  This  view  does  not  exclude  the  fact 
that  stimuli  can  also  occur  and  act  within  an  organism.  If  a  ner- 
vous impulse  is  conducted  from  the  cerebral  cortex  through  the 
pyramidal  tract  to  a  skeletal  muscle,  this  impulse  acts  upon  the 


THE  NATURE  OF  STIMULATION  37 

muscle  cells  as  a  stimulus.  Although  the  explosion  of  the  im- 
pulse is  an  alteration  within  the  body,  nevertheless,  as  far  as  the 
muscle  is  concerned,  it  may  be  looked  upon  as  an  external  vital 
condition,  therefore  as  a  stimulus.  As  the  conception  of  stinuilus 
involves  the  relation  to  a  given  state,  it  likewise  involves  at  the 
same  time  the  relation  to  a  given  living  system,  upon  which  it  acts 
from  the  exterior. 

What  is  the  value  then  of  all  this  theoretical  discussion? 

In  presenting  the  conception  of  stimulation  from  a  conditional 
standpoint,  I  desired  to  show  what  difficulties  stand  in  the  way 
of  a  theoretical  isolation  of  a  fundamental  conception  in  the  field 
of  physiology,  which  indeed  is  used  in  our  practical  research 
work  at  every  step.  ''Natura  non  facit  saltus."  I  wished  to 
demonstrate  that  the  sharp  separation  of  the  conception  of  stimu- 
lation, like  all  artificial  divisions  wdiich  we  make  in  nature,  must 
always  contain  an  arbitrary  note,  as  in  reality  isolated  systems 
do  not  exist  in  the  w^orld.  I  wished  to  show  that,  for  this  reason, 
the  conception  of  vital  system,  the  conception  of  life,  the  con- 
ception of  vital  conditions  are  not  sharply  defined.  I  wished 
likewise  to  show  that  as  a  necessary  consequence  of  this  fact 
a  sharp  separation  of  the  conception  of  stimulation,  which  can 
only  be  made  in  relation  to  that  of  vital  conditions,  cannot  be 
maintained  theoretically.  I  wished  to  show  further  that  there 
is  no  sharp  line  of  division  between  inner  and  outer  vital  con- 
ditions, and  that  we  cannot,  therefore,  make  a  strictly  theoretical 
distinction  between  the  conception  of  stimulation  and  that  of 
the  processes  of  development.  I  wished  to  show  that,  for  these 
reasons,  we  must  not  expect  from  the  conception  of  stimulation, 
as  we  understand  it,  anything  beyond  its  possibilities.  But  finally 
I  wished  also  to  show  that,  whilst  fully  conscious  of  and  with 
due  consideration  of  all  these  difficulties,  it  is  possible  to  work 
out  a  definition  of  stimulation  which  is  of  great  practical  work- 
ing value.  The  definition  in  short  is:  ''Stimulus  is  every  altera- 
tion in  the  external  vital  conditions." 

This  definition  gives  to  the  conception  of  stinuilation  its  most 
complete,  that  is  to  say,  its  generally  applicable  and  simplest 
form.     The  great  importance  from  a  methodical  standpoint  of 


38  IRRITABILITY 

this  definition  of  stimulation  for  the  research  of  Hfe  is  evident. 
Our  whole  experimental  natural  science  always  employs  for 
investigation  of  any  state  or  process  the  same  method :  the  state 
or  process  to  be  observed  is  studied  under  systematically  altered 
conditions.  By  stimulating  the  living  substance  it  is  brought 
under  changed  external  conditions.  A  systematic  employment 
of  stimulus  is,  therefore,  the  experimental  means  for  the  research 
of  life. 


CHAPTER   III 

THE  CHARACTERISTICS  OF  STIMULI 

Contents:  The  quality  of  the  stimulus.  Positive  and  negative  alterations 
of  the  factors  which  act  as  vital  conditions.  Extent  of  the  alteration 
in  vital  conditions  or  intensity  of  the  stimulus.  Threshold  stimuli, 
sub-threshold,  submaximal,  maximal  and  supermaximal  intensities  of 
stimulus.  Relations  betv^^een  the  intensity  of  stimulus  and  the  amount 
of  response.  The  Weber  and  Fechner  law.  All  or  none  law.  Time 
relations  of  the  course  of  the  stimulus.  Form  of  individual  stimulus. 
Absolute  and  relative  rapidity  in  the  course  of  the  stimulus.  Duration 
of  the  stimulus  after  reaching  its  highest  point.  Adaptation  to  per- 
sistent stimuli.  Series  of  individual  stimuU.  Rhythmical  stimuli. 
The  Nernst  law. 

We  have  found  that  stimuli  are  alterations  in  the  external  vital 
conditions  and  that  the  irritability  of  living  substance  consists  in 
the  capability  to  respond  to  stimuli  by  changes  of  the  vital  pro- 
cesses. It  now  behooves  us  in  the  interest  of  experimental 
research  to  investigate  the  relations  between  the  nature  of  the 
alterations  in  the  external  vital  conditions  on  the  one  hand,  and 
that  of  the  alterations  of  the  vital  process  on  the  other ;  that  is  to 
say,  to  systematically  study  the  effects  of  stimulation  on  the  living 
organism.  For  this  purpose  it  is  above  all  necessary  to  become 
acquainted  with  the  almost  countless  numbers  of  alterations 
which  take  place  in  the  external  vital  conditions  of  an  organism, 
and  to  create  a  systematic  scheme  of  stimulation  which  dilYeren- 
tiates  and  presents  in  comprehensive  order  those  various  ele- 
mentary factors  which,  among  the  innumerable  varieties  of  stim- 
uli, would  prove  effectual.  For  this  purpose  it  is  necessary  to 
select  the  various  factors  which  are  involved  in  an  alteration  of 
the  external  vital  conditions. 

The  first  of  these  factors  is  the  quaUty  of  the  stimulus.  The 
external  vital  conditions  are,  in  short,  a  series  of  chemical  factors, 
such  as  foodstuffs,  water  and  oxygen ;  the  presence  of   a  cer- 


40  IRRITABILITY 

tain  temperature ;  the  existence  of  a  certain  light  intensity ;  the 
existence  of  a  definite  static  pressure ;  and  finally  the  presence  of 
an  equal  osmotic  pressure.  The  stimulus  according  to  its  quality 
can  be  differentiated  into  chemical,  thermal,  photic,  mechanical 
and  osmotic  varieties.  To  these  must  be  added  other  forms  of 
stimuli  not  ordinarily  operative,  for  instance,  many  uncommon 
chemicals,  and  certain  kinds  of  rays.  The  form  of  stimulation, 
par  excellence,  which  has  acquired  the  greatest  importance  for  the 
experimental  investigation  of  life,  is  electricity.  In  its  manifold 
forms  it  permits,  as  no  other,  of  such  fine  gradations  of  inten- 
sity and  duration  that  it  has  become  in  the  hand  of  the  physiolo- 
gist an  invaluable  means  of  research. 

Alterations  in  those  factors  which  act  as  vital  conditions  com- 
pose the  great  mass  of  physiological  stimuli  which  act  continu- 
ously on  every  living  organism.  The  first  point  to  be  considered 
in  every  alteration  is  its  direction.  The  alterations  produced  by 
stimuli  may  be  of  two  different  kinds,  either  positive  or  negative. 
The  quantity  of  foodstuffs,  water  or  oxygen,  in  the  surrounding 
medium,  can  undergo  an  increase  or  diminution;  as  may  the 
temperature,  intensity  of  light,  the  atmospheric  and  osmotic  pres- 
sure. The  strength  of  the  electric  current,  which  may  be  applied, 
can  also  be  regulated.  In  accordance  with  the  definition  of  stimu- 
lation already  referred  to,  we  must  consider  these  alterations, 
whether  negative  or  positive,  as  forms  of  stimulation.  Now  the 
question  arises:  Is  this  point  of  view  justifiable?  Should  one 
also  consider,  for  example,  the  lessening  or  total  removal  of  a 
vital  condition  as  a  stimulus?  Should  one  consider  the  removal 
of  water  or  oxygen,  cooling  or  darkening,  as  a  stimulus  ?  It  has, 
in  point  of  fact,  been  occasionally  attempted  not  to  regard  these 
negative  deviations  as  forms  of  stimuli.  These  observers  per- 
mitted themselves  to  be  led  by  the  dogma,  that  only  that  which 
produces  an  excitation,  that  is,  an  increase  of  the  processes  in  the 
living  substance,  should  be  regarded  as  a  stimulus.  Such  a  limi- 
tation of  the  conception  of  stimuli  would  only  result  from  the 
one-sided  consideration  of  an  all  too  limited  circle  of  facts.  Con- 
sidered from  the  point  of  view  which  results  from  a  broader 
range  of  experience,  this  narrow  view  becomes  untenable. 


THE  CHARACTERISTICS  OF  STIMri.I  41 

In  the  first  place  it  does  not  follow  that  only  positive  fluctua- 
tions of  a  factor,  acting  as  a  vital  condition,  result  in  excitation 
in  the  existing  vital  processes.  The  ivithdraival  of  water  pro- 
duces a  diametrically  opposite  effect.  .'\  muscle,  from  which 
water  has  been  removed,  if  exjjosed  to  dry  air  or  placed  in  a 
hypertonic  salt  solution,  shows  violent  excitation,  which  manifests 
itself  in  great  increase  of  irritability  and  develoi)ment  (jf  lil)rillary 
contractions.  The  breaking  of  a  constant  current  which  has  for 
a  long  time  flowed  through  a  nerve  or  muscle  also  elicits  a 
momentary  excitation.  Further,  the  abrupt  removal  of  light 
may  also  bring  about  stimulation.  To  cite  an  example  from 
the  physiology  of  the  single  cell,  I  should  like  to  call  to  your 
attention  the  interesting  observations  of  Engelmann^  on  the 
Bacterium  photometricum,  of  which  he  was  the  discoverer. 
When  the  field  containing  these  organisms  is  suddenly  darkened, 
all  the  individuals  contained  in  the  drop  immediately  dart  forward 
for  some  distance,  at  the  same  time,  as  is  usually  the  case,  quickly 
rotating  around  their  own  axis,  and  then  after  a  moment  of 
immobility,  swim  on  quickly  in  another  direction.  An  analogous 
responsivity  has  also  been  shown  by  other  single  cell  organisms, 
as  has  been  pointed  out  by  several  observers  and  especially  by 
Jennings.'^  In  all  these  cases  the  excitation  was  produced  by  a 
lessening  or  total  withdrawal  of  the  factors  which  act  as  vital 
conditions ;  and  even  those  who  take  the  standpoint  that  only  such 
factors  are  to  be  considered  as  stimuli  which  produce  an  exciting 
eiYect,  are  compelled  to  regard  these  alterations  as  stimuli,  in 
spite  of  the  fact  that  they  are  negative  variations  of  external 
vital  conditions. 

But  further,  the  restriction  of  the  term  stimulation  to  those 
alterations  which  increase  the  course  of  the  changes  in  the  living 
substance  involves  the  observer  in  still  greater  contradictions. 
It  can  easily  be  shown  that  one  and  the  same  factor  in  one  and 
the  same  form  of  living  substance  has  now  an  exciting,  ntnv  a 
depressing  effect  on  the  vital  processes.    This  fact  can  be  readily 

1  Th.  W.  Engelmann:  "Bacterium  photometricum  cin  Bcitrag  zur  vcrglcichcndcn 
Physiologic  des  Licht-und  Farbensinns."     In   Pflugcrs  .Xrchiv.    lid.  30.  1883. 

2  Jennings:  "Behavior  of  the  lower  organisms."     New  Vork   1906. 


42  IRRITABILITY 

demonstrated^  by  means  of  the  infusoria  Colpidium  colpoda, 
which  can  be  grown  without  difficulty  in  a  hay  infusion.  A 
number  of  individuals  in  a  drop  of  fluid  may  be  placed  in  a 
warm  stage  and  observed  under  the  microscope;  one  then  sees 
that  at  room  temperature  they  swim  about  by  moving  their  ciliary 
processes  at  a  definite  rate.  Now  if  the  temperature  is  raised  to 
about  35°  C,  the  ciliary  movement  becomes  enormously  increased. 
The  infusoria  swim  madly  through  the  field  of  vision.  They  are 
in  a  state  of  violent  excitement.  The  increase  has,  therefore, 
acted  as  a  strong,  exciting  stimulus.  But  if  one  allows  the  tem- 
perature to  further  increase  only  a  few  degrees  the  ciliary  move- 
ments are  suddenly  greatly  retarded.  The  infusoria  now  swim 
sluggishly  through  the  field  of  vision  and  finally  remain  station- 
ary. In  this  case  the  increase  in  the  temperature  has  had  a  depress- 
ing effect.  If  the  infusoria  are  not  quickly  removed,  the  depression 
is  followed  by  death.  Should  the  increase  in  temperature  be 
regarded  in  the  first  instance  as  a  stimulus,  and  not  as  such  in  the 
second,  in  which  the  temperature  rises  only  a  few  degrees  higher  ? 
Here  the  change  in  the  vital  conditions  concerned  is  in  both 
instances  positive.  In  all  cases  of  overstimulation  we  are  con- 
fronted by  the  same  question.  Nevertheless  it  is  not  at  all  neces- 
sary to  refer  to  such  strong  or  even  life-endangering  stimuli  for 
the  observation  of  these  conditions.  In  this  connection  I  would 
like  to  cite  an  even  more  striking  instance  and  which  is  of  special 
interest  for  the  understanding  of  the  phenomena  in  nerve  centers. 
If  the  posterior  spinal  roots  of  a  Rana  temporara  are  severed,  and 
the  eighth  root  stimulated  with  a  faradic  current,  whilst  the  mus- 
culus  Gastrocnemius  of  the  same  side  is  connected  with  a  writing 
lever,  one  obtains,  as  Veszi~  has  found,  at  the  moment  of  the 
beginning  of  stimulation  a  contraction  of  the  muscle.  The  faradic 
stimulus  has,  therefore,  produced  an  excitation  reflexly.  If  instead 
of  the  eighth  the  ninth  posterior  root  is  stimulated,  the  result 
obtained  is  also  an  excitation  of  the  muscle.  In  this  case,  how- 
ever, the  excitation  in  the  form  of  a  tetanic  contraction  lasts  for 

1  Max   Verworn:  "Physiologisches  Prakticum  fur  Medizinen."     Jena  1907. 

2  Julius    Veszi:   "Der   einfachste    Reflexbogen    im    Riickenmark."       In   Zeitschrift    f. 
allgemeine  Physiologic  Bd.  XI,   1910. 


THE  CHARACTERISTICS  OF  STIMULI 


43 


some  time,  provided  that  the  stimulation  is  not  at  once  stopped.  H 
now  during  tetanic  stimulation  of  the  ninth  root  the  cij^dnh  is  at 
the  same  time  stimulated,  with  a  strength  of  current  equal  to 
that  which  previously  hrought  ahout  contraction  of  the  muscle, 


Fig.  2. 

Lower  thick  line  shows  duration  of  stimulation  of  9th  root;    upper  thick  line  that  of 

8th  root. 


instead  of  an  increase  and  a  strengthcti'uiy  of  contraction  there 
is,  on  the  contrary,  an  inhibition  which  continues  throughout  the 
time  during  the  stimulation  of  the  eighth  root.  If  the  stimulation 
of  the  eighth  root  is  discontinued,  the  tetanic  response  of  the 
ninth  root  reappears.  If,  on  the  other  hand,  the  faradic  stimu- 
lation of  the  ninth  root  is  interrupted  and  the  eighth  root  now 
again  stimulated,  one  obtains  once  more,  as  in  the  begiiming.  with 
each  stimulation  a  contraction  of  the  muscle.  This  fact  is  illus- 
trated by  the  accompanying  tracings.  (Figure  2.)  In  this  inves- 
tigation undertaken  in  the  Gottingen  laboratory  it  was  further 
shown  that  a  faradic  current  of  the  same  strength  and  the  same 
frequency  had  at  one  time  an  augmenting,  at  another  an  inhibitory 
effect,  and  these  eft'ects  could  be  jiroduced  alternately  at  will. 
Should  the  faradic  current  at  one  time  be  called  a  stimulus,  at 
another  not?  It  is  here  clearly  shown  to  what  absurd  conse- 
quences it  leads  if  the  conception  of  stimulation  is  limited  solely 
to  the  cases  in  which  an  external  factor  has  an  exciting  eflecl ; 


44  IRRITABILITY 

and  yet  an  immense  number  of  instances  of  a  like  nature  could 
be  cited  to  show  the  untenability  of  this  view. 

It  follows  from  this,  that  it  is  altogether  impracticable  to  define 
the  stimulus  itself  in  relation  to  the  nature  of  the  effects  which 
the  stimulus  has  upon  the  substances  in  the  living  system.  One 
can  only  appreciate  the  nature  of  stimulation  in  relation  to  the 
vital  conditions  and  without  considering  the  nature  of  the  action 
of  the  stimuli  on  the  living  substance.  It  is  true  that  every 
stimulus  is  followed  by  an  alteration  in  living  processes,  but  this 
is  to  be  expected  when  one  clearly  understands  the  nature  of 
vital  conditions.  A  stimulus  is  in  all  cases  an  alteration  in  vital 
conditions  and,  in  that  each  of  the  vital  conditions  is  necessary  for 
the  continuance  of  life,  it  follows  of  necessity  that  every  altera- 
tion in  the  vital  conditions,  so  intimately  connected  with  the 
living  processes,  will  also  be  followed  by  an  alteration  in  the 
processes  occurring  in  the  living  system.  In  short,  response  is 
produced.  Nevertheless,  a  definite  alteration  of  an  external  vital 
condition,  depending  upon  the  state  of  other  vital  conditions, 
that  is,  according  to  the  state  of  living  substance  at  the  moment, 
can  produce  quite  opposite  effects.  Although  it  may  appear 
expedient  to  include  in  the  conception  of  stimulation  in  given 
instances,  distinctions  between  stimuli  according  to  the  nature 
of  their  effects  upon  the  living  substance,  in  all  cases  the  con- 
ception must  under  all  circumstances  be  so  formulated  that  it 
comprises  all  alterations  in  the  external  vital  conditions,  either 
positive  or  negative,  that  is  to  say,  an  increase  or  decrease,  an 
augmentation  or  diminution  in  those  factors,  acting  as  vital 
conditions. 

Besides  the  quality  there  is  another  highly  important  factor 
to  be  considered  in  the  study  of  every  alteration  in  the  living 
process,  namely,  its  amount.  The  chemical  concentration  of  the 
medium,  temperature,  amount  of  light,  the  static  and  osmotic 
pressure  may  undergo  more  or  less  variation.  The  electric 
stimulus  can  rise  from  zero  to  great  intensity  and  from  great 
intensity  can  fall  to  zero.  The  extent  of  the  alteration  deter- 
mines the  intensity  of  the  stimulus.  In  relation  to  the  intensity, 
a  differentiation  of  stimulation  has  been  introduced,  which  is  not 


THE  CHARACTERISTICS  OF  STIMULI  45 

dependent  upon  the  absolute  intensity  of  the  stinuihis,  that  is, 
upon  the  extent  of  the  alterations  in  the  external  vital  conditions, 
but  the  intensity  of  the  response  that  can  be  observed.  One 
refers  frequently  to  threshold  stimulation,  to  stimulation  beneath 
the  threshold,  to  submaximal,  maximal  and  supcrmaximal  stimu- 
lation. Such  a  classification  is  in  many  ways  very  valuable.  It 
is  not  only  of  practical  value  for  the  establishment  of  definite 
intensities  of  stimulation,  but  also  for  the  study  of  the  state  of 
irritability  in  the  living  organisms. 

The  threshold  of  stimulation  furnishes  roughly  a  standard  for 
the  degree  of  irritability  of  a  living  system.  The  threshold  value 
of  a  stimulus  is  then  that  degree  of  intensity  which  is  just  sutYi- 
cient  to  bring  about  a  perceptible  response.  The  threshold  of 
stimulation  is  low,  that  is,  the  irritability  is  great,  when  the  inten- 
sity of  the  threshold  stimulus  is  small;  the  threshold  is  high, 
that  is,  the  irritability  of  a  system  is  small,  if  the  intensity  of  the 
threshold  stimulus  is  great.  All  intensities  of  stimuli  beneath  the 
threshold  are  sub-threshold  stimuli.  Here  a  point  must  not  be 
overlooked,  which  in  older  physiology  did  not  generally  meet 
with  sufficient  attention.  From  the  fact  that  the  sub-threshold 
stimuli  produce  no  apparent  effects,  the  wrong  deduction  must 
not  be  made,  that  they  have  no  effect  whatsoever.  The  concep- 
tion of  the  threshold  of  stimulation  originated  in  the  field  of 
muscle  physiology  and  that  of  the  special  senses.  Here  the  indi- 
cator of  the  response  is,  on  the  one  hand,  contraction  of  the 
muscles,  and  on  the  other,  conscious  sensation.  There  was  a 
great  temptation  to  consider  the  stimulus  altogether  ineffectual, 
if  it  produced  no  conscious  sensation  or  no  contraction  of  the 
muscle.  Today  with  our  finer  and  more  sensitive  indicators  for 
the  study  of  the  alterations  in  the  living  substance,  we  know  in 
reality  that  sub-threshold  stimuli,  which  i)roduce  no  apparent 
effect  in  the  living  substance,  can  have  an  effect  in  reality. 

I  will  call  your  attention  later  to  the  fact  that  these  sub- 
threshold stimuli  play  a  very  important  role  under  certain  condi- 
tions in  the  activities  of  the  central  nervous  system.  It  only 
depends  upon  the  sensitivity  of  our  special  senses,  or  the  indi- 
cators used  for  this  purpose,  as  to  whether  the  alterations  can 


46  IRRITABILITY 

be  observed  or  not.  The  conception  of  the  threshold  of  stim- 
ulation, therefore,  has  meaning  only  when  used  in  relation  to 
a  certain  indicator.  The  threshold  of  the  same  living  system 
may  be  different  for  different  indicators.  When  we  use  the 
term  threshold  we  must  necessarily  know  the  indicator  employed 
in  its  determination.  The  threshold  stimulus  produces  only 
barely  perceptible  effects.  The  amount  of  response  in  most 
living  substances  increases  with  the  intensity  to  a  certain  limit. 
If  this  Hmit  is  reached,  that  is,  if  the  response  is  maximal,  the 
stimulus  of  the  weakest  strength  necessary  to  produce  this  result 
is  termed  the  maximal  stimulus,  whereas  all  intensities  lying 
between  the  threshold  and  the  maximal  stimulus  are  termed 
suhmaximal  stimuli.  If  the  intensity  of  the  stimulus  is  increased 
above  that  of  the  maximal,  the  response,  as  in  the  case  of  the 
muscle,  does  not  increase,  and  therefore  one  could  say  that  all 
intensities  above  the  maximal  could  also  be  called  maximal 
stimuli. 

In  realty,  however,  the  response  to  stimuli  of  different  inten- 
sities is  never  equal,  even  though  it  may  appear  so,  when  meas- 
ured by  an  indicator,  as  for  instance,  the  height  of  the  maximal 
muscle  contractions.  This  is  clearly  shown,  for  example,  when 
the  electrical  stimulus  is  increased  far  beyond  that  intensity  which 
is  necessary  to  produce  maximal  effect.  Injury  is  thereby  pro- 
duced, which  is  manifested,  for  instance,  in  the  muscle  contrac- 
tion by  the  nature  of  its  course  and  also  by  its  height.  One  is, 
therefore,  justified  in  a  certain  sense  in  calling  the  intensities  of 
the  stimulus,  which  are  above  the  value  which  barely  produces 
maximal  contraction,  "supermaximal  stimuli,"  notwithstanding 
this  is  logically  far  from  being  a  happy  expression.  The  term 
"maximal  stimulus,"  then,  is  limited  to  the  intensity  of  the  stimu- 
lus which  just  produces  a  maximal  effect.  I  wish  to  point  out  this 
distinction  between  maximal  and  supermaximal  stimulus,  as  there 
is  often  a  lack  of  clearness  in  the  use  of  these  terms. 

In  that  the  nomenclature  of  intensity  of  stimulation  is  based 
upon  the  intensity  of  response,  the  question  arises  as  to  the  rela- 
tion between  the  intensity  of  stimulus  and  the  amount  of  response. 
It  is  well  known  that  this  question  has  met  in  one  special  field 


THE  CHARACTERISTICS  OF  STIMULI  47 

of  physiology  with  a  very  detailed  and  comprehensive  treatment. 
I  allude  to  the  teaching  concerning  sensation.  Ernst  llcmrich 
Weber^  first  called  attention  to  the  relation  between  increase  in 
sensation  and  that  of  the  stimulus  in  the  case  of  the  sense  of 
touch.  His  observations,  which  have  been  formulated  into 
''Weber's  law,"  have  been  the  object  of  animated  discussion.  A 
presentation  of  this  law  is  the  following:  "The  amount  of  pres- 
sure necessary  to  produce  a  perceptible  increase  of  sensation 
always  bears  the  same  ratio  to  the  amount  of  the  stimulus  already 
applied." 

If  in  accordance  with  Ziehen'-  we  designate  the  relative 
increase  in  pressure  to  that  already  applied,  which  is  necessary 
to  produce  a  perceptible  increase  in  sensation,  as  the  threshold  of 
relative  differentiation,  we  can  formulate  the  law  in  the  simplest 
way  thus:  The  relative  threshold  of  differentiation  is  constant. 
Fechner,^  who  indeed  attempted  to  apply  this  law,  applical)le  to 
the  sense  of  pressure,  to  all  the  other  special  senses,  has  given 
us  a  mathematical  formula,  based  on  the  assumption  that  the  just 
perceptible  increase  of  sensation  has  the  same  value  at  all  levels. 
By  this  assumption  he  was  able  to  establish  for  the  first  time  a 
relation  between  the  intensity  of  sensation  and  that  of  stimulus, 
for  it  follows  that  ''the  sensation  increases  in  intensity  in  arith- 
metical progression,  whereas  the  intensity  of  the  stiinulns  in- 
creases in  geometrical  progression."  From  this  Fechner  has 
worked  out  a  psychophysical  formula,  which  today  is  generally 
termed  the  Fechner  laiv.  This  is  the  law :  The  intensity  of  sensa- 
tion varies  with  the  logarithm  of  the  intoisity  of  the  stimulus. 

Soon  the  Weber  as  well  as  the  Fechner  law  had  been  extended 
over  the  whole  field  of  sensation  and  stimulation.  In  this  con- 
nection Preyer^  has  formulated  his  "myoi)hysical  law."  which 
states  that  there  is  the  same  relation  between  strength  of  stimulus 
and  the  intensity  of  response  of  the  nui.scle  as  is  laid  down  by  the 

1  Weber:  "Annotationes  anatomicx  et  physiologica-."  Lips.  1851.  The  s.imc:  "Der 
Tastsinn  und  das  Gemeingefuhl,"  in  Wagner's  Handw^rterbuch  d.  Physiologic  Bd.  III. 
2.     Braunschweig  1846. 

2  Ziehen:    "Leitfaden    der    physiologischen    Psychologic    in    15    Vorlcsungcn."        VI 

Auflage.     Jena   1902. 

3  Fechner:  "Elemente  der  Psychophysik."     Leipzig  1860.     2  Auflage   1889. 
4Preyer:  "Das  myophysische  Gesetz."     Jena    1874. 


48  IRRITABILITY 

Fechner  law  for  stimulation  and  sensation.  Pfeffer^  has  found 
that  Weber's  law  applied  also  to  the  relations  of  the  chemotaxis 
of  bacteria,  to  the  intensity  of  the  chemical  stimulus,  and  likewise 
the  attempt  has  been  made  to  show  that  all  living  substances 
respond  in  the  manner  laid  down  by  the  Weher-Fechner  law. 
Unfortunately  the  innumerable  investigations  in  this  field  have 
shown  more  and  more  clearly  that  it  is  not  possible  to  formulate 
a  general  mathematical  law,  which  strictly  fixes  the  relations  of 
the  intensity  of  the  stimulus  and  the  intensity  of  response.  Even 
in  the  field  of  the  physiology  of  the  special  senses  many  voices 
have  opposed  the  general  application  of  the  Weber  and  the 
Fechner  law.  Lotze,  G.  Meissner,  Dohrn,  Hering,  Biedermann 
and  Lowitt,  Funke  and  numerous  other  investigators  have  already 
demonstrated  for  some  decades,  partly  by  means  of  critical 
inquiry,  partly  by  experimentation,  that  these  laws  are  not  strictly 
valid.  Above  all  these  experiments  have  shown  that  logarithmic 
relations  are  not  tenable  and  likewise  are  not  applicable  to  very 
strong  stimuli.  The  assumption  made  by  Fechner,  that  is,  the 
acceptance  that  all  barely  perceptible  increases  of  sensation  have 
an  equal  value,  has  been  set  aside  as  incorrect,  and  with  this  his 
mathematical  formulation  within  those  boundaries  of  intensity 
of  the  stimulus,  in  which  the  Weber  law  has  proven  itself  valid, 
must  also  be  abandoned.  That  which  we  can  say  today  with  cer- 
tainty concerning  the  relation  between  the  intensity  of  stimulus 
and  the  amount  of  response  is  as  follows :  A  law  generally  appli- 
cable to  the  relation  between  the  strength  of  the  stimulus  and 
the  amount  of  response  cannot  be  mathematically  formulated. 
For  a  great  number  of  living  systems  the  rule  which  holds  for 
the  intensity  of  stimulation  within  certain  boundaries  is  the  fol- 
lowing :  With  increase  of  the  intensity  of  stimulation  the  response 
at  first  increases  rapidly  and  later  more  and  more  slowly. 

This  rule  of  course  only  applies  within  the  boundaries  of  the 
intensity  between  the  threshold  of  stimulation  and  maximal 
stimulus.    The  interval,  however,  between  these  intensities  varies 

1  Pfeffer:  "Ueber  chemotaktische  Bewegungen  von  Bacterien,  Flagellaten  und 
Volvocineen."  Untersuchungen  aus  dem  botanischen  Institut  zu  Tubingen.  Bd.  II, 
1888. 


THE  CHARACTERISTICS  OF  STIMULI  4!) 

considerably  in  different  living  substances.  In  iliis  connection 
there  are  several  forms  of  living  substance  which  call  for  our 
special  attention.  In  these  the  suri)rising  condition  seems  to  exist, 
that  the  interval  between  the  threshold  and  the  maximal  stimulus 
is  zero;  that  is,  every  stimulus  which  acts  at  all  always  })rf)duces 
a  maximal  response.  Bozvditch^  first  observed  this  behavior  in 
the  frog's  heart  and  this  has  also  been  confirmed  by  Kroncckcrr 
The  induction  current  produces,  as  Boivditch  says,  cither  a  con- 
traction or  nothing.  If  the  former,  it  is  the  strongest  contrac- 
tion which  can  be  produced  by  an  induction  shock  at  the  given 
time.  Here  for  the  first  time  a  constancy  of  response  was  dis- 
covered which  has  been  termed  the  all  or  none  lazu.  Mcll'illiams^ 
has  later  verified  the  same  fact  for  the  mammalian  heart. 
Gotch'^  has  also  arrived  at  the  same  conclusion  in  connection  with 
the  nerve.  He  states  that  "the  comparison  of  submaximal  with 
maximal  responses  shows  that  although  there  is  an  obvious  differ- 
ence in  the  amount  of  E.  M.  F.,  there  is  little  or  no  difference 
between  such  time  relations  as  the  moment  of  commencement,  the 
moment  of  culmination  of  E.  M.  F.  and  the  rate  at  which  E.  M.  F. 
disappears."  Further:  *'the  rate  of  propagation  of  the  excitatory 
wave  is  the  same  whether  this  is  maximal  or  submaximal."  He 
likewise  assumes  that  the  '*all  or  none  law"  is  a])plicable  to  the 
constituent  fibers,  and  that  the  variations  in  the  strength  of 
response  with  weak  and  strong  stimulation  are  brought  about 
in  the  first  instance  by  stimulation  of  a  few,  in  the  latter  by 
a  greater  number  of  fibers  in  the  nerve  trunk.  The  same  con- 
clusion has  been  reached  by  Keith  Lucas-'  for  the  single  cross- 
striated  fiber  of  the  skeletal  muscle,  founded  on  the   fact  that 

1  Bowditc It:  "Ueher  die  Eigentiimlichkeiten  der  Rtizbarkeit,  wclchc  die  Muskcl- 
fasern  des  Herzens  zeigen."  In  Arbeiten  aus  der  physiologischen  Anstalt  zu  Leipzig 
VI.     Jahrgang  1872. 

2  Kroneckcr:  "Das  characteristische  Merkmal  der  Herzmuskelbcwegung."  In 
Beitrage  zur  Anat.  und  Physiol.  Als.  Festgabe  Carl  Ludwig  gewidmet  von  seinen 
Schiilern.     Leipzig  1874. 

3  MclVilliams:  "On   the   rhythm   of   the   mammalian   heart."     Journal   of   Physiology. 

Vol.   IX,   1888. 

4Gotch:  "The  submaximal  electrical  response  of  nerve  to  a  single  stimuhi*." 
Journal   of   Physiology,   Vol.    XXVIII,    1902. 

5  Keith  Lucas:  "On  the  graduation  of  activity  in  a  skeletal  muscle  fibre."  Journal 
of   Physiology,  Vol.   XXXIII,    1905-06. 


50  IRRITABILITY 

by  direct  stimulation  of  a  bundle  of  curarized  muscle  fibers, 
the  contraction  only  increases  inconstantly  and  not  regularly 
with  the  increasing  intensity  of  the  stimulus.  This  is  only 
comprehensible  if  one  takes  into  consideration  that,  with  the 
increasing  intensity  of  the  stimulus,  a  greater  and  greater  number 
of  fibers  are  stimulated.  Keith  Lucas^  came  to  the  same  con- 
clusion in  the  case  of  the  muscle  stimulated  indirectly  through 
the  nerve.  He,  therefore,  sees,  because  of  the  nature  of  the 
response  of  the  single  muscle  cell,  no  difference  between  heart 
muscle  and  skeletal  muscle.  The  ''all  or  none  law"  applies  to  the 
individual  muscle  cells  of  both  kinds.  The  difference  between 
the  heart  and  skeletal  muscle,  according  to  him,  lies  in  the  fact 
that  in  the  heart  the  individual  muscle  cells  in  their  totality  stand 
together  as  conductors  of  excitation,  whereas  in  the  skeletal 
muscle  the  individual  muscle  fibers  are  separated,  as  far  as  con- 
duction of  excitation  is  concerned,  by  the  sarcolemma.  Finally, 
the  recent  investigations  of  Veszr  with  strychnine  poisoned  gan- 
glia cells  of  the  posterior  horns  of  the  spinal  cord,  have  made  it 
appear  probable  that  "the  all  or  none  law"  can  be  appHed  like- 
wise to  the  individual  ganglion  cell.  He  draws  this  conclusion 
not  only  from  the  fact  that  all  reflex  contractions  of  a  muscle 
of  a  strychninized  frog  are  maximal,  whether  they  are  produced 
by  weak  or  strong  stimuli,  but  also  especially  because  of  the 
loss  in  the  strychninized  spinal  cord  of  the  capacity  of  the  summa- 
tion of  irritability.  The  normal  spinal  cord  does  not  reflexly 
respond  at  all  to  weak  single  stimuli,  but  responds  to  equally 
weak  faradic  stimulation  very  readily.  Therefore,  the  threshold 
lies  very  high  for  the  individual  induction  shock  and  very  low 
for  faradic  shocks.  But  these  dififerences  are  equalized  in  the 
strychninized  frog.  This  seems  intelligible,  when  we  assume 
that  the  strychninized  cell  responds  to  every  stimulus,  to  which 
it  responds  at  all,  to  the  maximal  extent  which  is  permitted  at 
that  moment  by  its  stored  up  energy,  otherwise  the  excitation 
would  necessarily  be  summated  by  faradic  stimulation. 

1  Keith  Lucas:  "The  all  or  none  contraction  of  skeletal  muscle  fibre."     Journal  of 
Physiology,  Vol.   XXXVIII,   1909. 

2  I'essi:  "Zur   Frage   des   Alles   oder   Nichts-Gesetzes   beim   Strychninfrosch."      Zeit- 
schrift  fiir  allgemeine  Physiologic  Bd.   XII,   1911. 


THE  CHARACTERISTICS  OF  STIMULI  51 

Such  are  the  instances  to  which  one  has  up  to  llic  present 
appHed  the  "all  or  none  law."  The  (juestion  if,  as  a  matter  of 
fact,  such  a  condition  has  ever  been  realized  in  any  living  sub- 
stance has  until  now  found  no  linal  answer.  Most  authors,  who 
accept  the  validity  of  the  "all  or  none  law"  for  certain  living  sub- 
stances, do  so  with  a  certain  reserve  and  speak  only  of  the  possi- 
bility or  probability  of  such  behavior.  'Hie  subject  has.  how- 
ever, as  will  be  shown  later,  a  great  and  even  vital  interest  in 
another  direction.  For  this  reason  I  should  prefer  to  postpone  the 
treatment  of  the  same  to  a  later  occasion.  Here  I  wish  simply  to 
say,  that  if  the  "all  or  none  law"  is  valid  in  a  strict  sense  for 
certain  structures,  then  there  exists  no  general  constancy  of  the 
relations  of  the  intensity  of  the  stimulation  and  the  amount  of 
response,  applicable  to  all  living  organisms. 

We  will  now  return  from  this  digression  concerning  the  rela- 
tions between  the  intensity  of  the  stimulus  and  the  response,  to 
the  further  characterization  of  the  properties  of  the  stimulus. 
Besides  the  quality,  the  direction  and  the  intensity  of  every  altera- 
tion in  vital  conditions,  an  equally  important  factor  is  the  dura- 
tion of  the  alteration.  The  time  relations,  under  which  a  devia- 
tion of  the  external  vital  conditions  takes  place,  present  immense 
and  manifold  variations  in  nature.  In  many  cases  the  change 
is  very  complicated,  as  for  instance,  the  alteration  of  the  static 
pressure  or  the  temperature  under  the  influence  of  air  or 
water  currents,  the  osmotic  pressure  or  chemical  factors  in 
diffusion  currents,  and  the  light  intensity  produced  l)y  the  move- 
ment of  clouds.  These  very  irregular  alterations  have  practically 
little  interest  for  us.  Here  we  are  concerned  rather  with  the 
differentiation  of  the  time  alterations  of  the  processes  of  the 
simplest  fundamental  types,  which  are  of  importance  in  studying 
the  course  of  the  reaction.  For  it  is  of  such  simple  elements 
that  the  complicated  and  irregular  alterations  of  the  above- 
mentioned  kinds  are  composed. 

The  simplest  form  of  an  individual  change  in  the  external 
vital  conditions  would  be  a  regular  and  constant  alteration  of 
intensity  which  can  be  graphically  represented  as  a  straight  line, 
wherein  the  intensities  are  the  ordinates  and  the  time  the  al)scissa. 


52 


IRRITABILITY 


(Figure  3,  A.)  A  regularly  rising  pressure  would,  for  instance, 
represent  a  stimulus  in  its  simplest  form.  But  such  forms  of 
stimuli  are  only  very  rare  in  nature  and  are  also  experimentally 
very  difficult  to  produce.  It  is,  for  example,  not  easy  to  give  the 
electrical  stimulus,  so  much  used  for  experimental  purposes,  this 
form.  Fleichl  and  v.  Kries  have  only  accomplished  this  by  means 
of  complicated  apparatus.  The  usual  form  of  the  individual 
stimulus  is  not  a  straight  line,  but  a  logarithmic  curve.  (Figure 
3,  B.)  The  alteration  hardly  ever  progresses  with  equal  rapidity 
from  its  beginning  until  it  reaches  its  highest  point,  but  as  a  rule, 
with  decreasing  rapidity.  This  is  the  usual  course  of  alterations 
of  concentration,  also  of  chemical  and  osmotic  stimuli,  of  changes 
of  temperature  and  of  electric  stimulation. 


Fig.  3. 


The  rapidity  of  alterations  in  vital  conditions  has  quite  an 
important  influence  on  the  development  of  the  response  to  stimu- 
lation. It  is  well  known  that  if  a  constant  current,  which  reaches 
its  highest  intensity  rapidly,  is  permitted  to  act  upon  a  muscle, 
the  effect  differs  from  that  following  the  application  of  a  current 
of  the  same  intensity  but  in  which  this  is  reached  very  slowly.  In 
the  first  case  there  is  a  sudden  strong  twitch,  in  the  second  none 
at  all.  In  spite  of  this  there  can  be  no  doubt  whatever  of  the 
current  in  the  last  case  being  effective.  That  the  muscle  is  also 
excited  when  the  current  is  slowly  increased  is  shown  by  the 
contracture,  which  grows  more  and  more  plainly  perceptible  with 
the  increasing  intensity  of  the  current  and  in  higher  intensities 
by  the  so-called  Porret's  phenomenon,  which  consists  in  a  curious 
wave-like  movement  of  the  muscle-substance.     In  reference  to 


THE  CHARACTERISTICS  OF  STIMULI  53 

the  rapidity  of  the  alterations  in  the  factors  which  act  as  stiniuh, 
the  behavior  varies  greatly.  Many  stimuli  because  of  their  nature 
never  have  a  steep  ascent  or  descent  of  intensity,  as,  for  instance, 
alterations  in  the  concentrations  of  soluble  substances,  that  is. 
chemical  or  osmotic  stimuli;  likewise  temperature  variati(jns  may 
be  mentioned.  They  always  act  relatively  slowly.  (  )n  the  con- 
trary there  are  forms  of  stimuli  which  have  now  a  rai)id,  now  a 
slow,  ascent  or  descent  of  their  intensity,  such  as  the  jjhotic  and 
mechanical  stimuli.  Finally,  there  are  other  stimuli  that  nearly 
always  show^  a  very  abrupt  change  of  intensity,  such  as  the 
electrical  form. 

The  most  important  factor  to  be  considered  in  producing  the 
response  to  variations  of  intensity,  is  not  the  absolute  rapidity,  but 
rather  the  relative  rapidity;  that  is,  the  rapidity  in  relation  to  the 
characteristic  rapidity  of  reaction  of  the  particular  living  sub- 
stance concerned.  The  rapidity  of  the  reaction  to  stinnili  is  very 
different  in  various  forms  of  living  substance.  ( )n  the  one 
hand,  we  have  forms  reacting  very  quickly,  as  the  nerve  and  the 
striated  muscle;  on  the  other,  those  which  respond  very  slowly, 
such  as  a  great  number  of  unicellular  organisms.  Between  these 
are  a  great  number  of  living  substances  which,  as  far  as  the 
rapidity  of  the  reaction  is  concerned,  occupy  intermediate  posi- 
tions of  every  varying  degree.  It  is  clear  that  the  adequate 
stimuli  for  slowly  reacting  substances  must  be  those  having  also 
a  slow  change  of  intensity;  for  quickly  reacting,  those  having  a 
rapid  change  of  intensity.^  If  a  nerve  muscle  preparation  is 
simulated  with  the  single  induction  shock,  the  "break"  as  well  as 
the  "make"  shock  has  effect.  But  even  here  a  difference  is 
noticeable.  The  ''make"  shock  has  a  weaker  effect  than  the 
''break"  shock.  This  difference  is  due  to  the  difference  of 
abruptness  in  its  course,  which  when  the  current  is  made  is  less 
than  that  of  opening,  for,  when  the  current  is  made,  the  ascent 
of  the  primary  current  is  retarded  by  the  extra  current  flowing 
in  the  opposite  direction,  whereas,  when  broken,  with  the  fall 
of  the  intensity  of  the  primary  current,  the  extra  current  in  the 

1  Vergl.   Julius   Sclwtt:   "Ein   Beitriig   zur   electrischen    Reigung   des   qucrgcstrciften 
Muskels  von  seinen  Nerven  aus."      Pflugers  Archiv   Bd.   48,   1891. 


54 


IRRITABILITY 


primary  coil  flows  in  the  same  direction.  In  consequence  of  this 
there  is  a  perceptible  difference  in  the  rapidity  of  the  alteration 
of  the  "make"  and  "break"  shocks.     (Figure  4.) 


Fig.  4. 

Course  of  induction  shocks.    1  and  2  make  and  break  of  the  primary  current, 
li  and  2i  make  and  break  induction  shocks.    (After  Hermann.) 


Now  slowly  reacting  forms  of  living  substance,  such  as  certain 
foraminifera,  in  which  the  extended  pseudopods  are  stimulated 
with  single  induction  shocks,  the  break  as  well  as  the  make 
shocks  are  wholly  without  effect,  as  both  take  place  far  too  quickly 
for  the  slow  responsivity  of  these  organisms.  I  have  made  such 
observations  on  various  forms  of  foraminifera  of  the  Red  Sea,  on 
Orbitolites,  Amphistegina  and  others.  The  movement  of  granules 
in  the  pseudopods  is  not  influenced  by  the  induction  shocks  in  the 
least.  It  also  continues  without  interruption  when  the  pseudopods 
are  extended.  Even  with  the  strongest  induction  shocks  at  my 
disposal  I  could  not  induce  them  to  contract ;  the  f aradic  current, 


o 


56  IRRITABILITY 

also,  the  intensity  of  which  I  found  quite  unbearable,  remained 
utterly  without  effect/  These  two  extreme  cases,  the  nerve  and 
the  foraminifera,  show  plainly  that  the  effect  of  a  stimulus  is  not 
produced  by  the  absolute  rapidity  of  the  increase  of  intensity,  but 
is  solely  influenced  by  the  relative  rapidity  of  the  same. 

A  further  point  for  consideration  in  the  duration  of  an  altera- 
tion in  a  vital  condition  in  producing  a  stimulant  action  is  the 
length  of  time  the  stimulus  remains  after  reaching  its  highest 
point.  In  the  forms  of  stimuli  occurring  in  nature  the  duration 
of  the  alteration  after  reaching  its  highest  level  can  vary  consider- 
ably. The  stimulus  may  remain  indefinitely  at  a  certain  level, 
when  this  is  once  reached.  (Figure  5,  A.)  The  alteration  like- 
wise persists.  This  would  be  the  case,  for  instance,  with  the 
changes  of  concentration  in  the  transfer  of  an  organism  from 
fresh  into  sea  water.  The  alteration  can  also,  however,  imme- 
diately after  attaining  its  highest  level,  return,  so  that  the  original 
state  is  at  once  reestablished.  (Figure  5,  B  and  C.)  Here  it  is  a 
case  of  a  quick  deviation  in  the  external  vital  conditions.  A 
sudden  jar  would  be  a  case  in  point.  Between  these  two  extremes 
we  have  all  variations  in  the  duration  of  all  natural  and  experi- 
mental forms  of  single  stimuli. 

Now  we  arrive  at  the  question:  Has  a  prolonged  stimulation 
really  a  prolonged  effect?  This  question  might  seem  superfluous, 
as  from  a  conditional  standpoint  it  is  self-evident  that  every 
alteration  in  any  one  of  the  conditions  of  a  system  is  followed 
by  an  alteration  in  the  system.  But  this  very  question  played  an 
important  role  in  older  physiology  and  led  to  prolonged  discus- 
sions for  the  reason  that  a  special  case  was  taken  into  considera- 
tion in  this  connection,  which  at  that  time  was  not  clearly  under- 
stood. Du  Bois-Reymond,-  as  a  result  of  his  investigations  on 
the  nerve  muscle  preparation  of  the  frog,  formulated  a  law  of 
nerve  excitation,  according  to  which  it  is  not  the  absolute  value 
of  the  intensity  of  the  constant  current  which  produces  an  exci- 
tation of  the  nerve  and  contraction  of  its  muscle,  but  an  alteration 

1  Max  Verworn:  "Untersuchungen  iiber  die  polare  Erregung  der  lebendigen 
Substanz  durch   den   constanten   Strom."      Ill  Mitteilung,   Pflugers  Arch.   Bd.   62,    1896. 

2  Du  Bois-Reymond:  "Untersuchungen  iiber  tierische  electricitat."  Bd.  I.  Berlin 
1848,  p.  258. 


THE  CHARACTERISTICS  OF  STIMULI  57 

of  the  intensity  from  one  moment  to  another.  The  more  rapidly 
these  changes  are  produced,  the  greater  is  the  excitati(jn.  His 
arguments  were  based  upon  the  fact  that  a  contraction  can  only 
take  place  on  the  "making"  or  "breaking,"  or  by  rapidly  streiigtii- 
ening  or  weakening  the  constant  current ;  it  is  possible  to  subject 
a  nerve  muscle  preparation  to  a  current  of  considerable  strength 
without  a  muscle  contraction  resulting,  provided  it  is  slowly 
increased.  One  might  be  disposed  to  conclude  from  this  that 
the  constant  current,  when  showing  no  fluctuations,  has  no  stinui- 
lating  effect  whatsoever.  Should  this  observation  be  carried 
even  further  and  the  attempt  made  to  extend  it  into  a  general  law 
of  excitation  by  assuming  that  the  effects  of  stimulation  are  only 
produced  by  variations  in  the  intensity,  not  by  its  contiiuicd 
duration,  one  would  commit  the  error  of  judging  the  occurrence 
of  a  stimulus  only  by  the  unsatisfactory  criterion  of  an  al)rupt 
muscle  contraction.  Today  we  know  with  positiveness  that  a 
continued  effect  also  exists  during  the  uninterrupted  flowing  of 
a  constant  current  in  nerve  or  muscle,  though  much  weaker,  how- 
ever, than  in  the  case  of  the  excitations  produced  by  sudden 
fluctuations  of  the  intensity.  This  is  shown  in  the  nerve  by  an 
altered  excitability,  which  continues  at  the  poles  during  the  whole 
duration  of  the  current.  In  the  region  of  the  anode  the  excita- 
bility is  diminished,  in  that  of  the  cathode  it  is  increased.  An 
excitation  can  also  be  demonstrated  which  extends  from  the 
cathode  through  the  nerve,  which  can  easily  be  detected  by 
sufficiently  delicate  methods.  Among  other  effects  of  prolonged 
stimulation  is  that  of  cathodal  contracture,  which  remains  local- 
ized in  the  region  of  the  cathode  and  which  excitation  persists  as 
long  as  the  current  continues.  This  permanent  excitation  can  be 
particularly  well  observed  in  the  single  cells  of  the  rhizopods. 
If  a  constant  current  is  allowed  to  flow  through  an  .Ictino- 
sphccrium,^  the  straight,  smooth,  ray-shaped  pseudopods  of  the 
cell  body  at  the  moment  of  "making,"  show  evidence  of  con- 
traction by  being  drawn  in,  particularly  those  directed  towards 

1  KUIiue:  "Untersuchungen  uber  das  Protoplasma  uiid  die  Contractilitat."  Leipzig 
1864.  Max  Verworn:  "Die  polare  Erregung  der  Protisten  durcli  dcr  galvanischcn 
Strom."     Pfliigers  Arch.   Bd.  35.  45.   1889. 


58 


IRRITABILITY 


the  anodic  and  in  less  degree  also  those  towards  the  cathodic 
pole.  This  excitation,  greatest  at  the  time  of  "making"  of  the 
current,  though  diminishing  rapidly  in  intensity  during  its  con- 
tinuance, remains,  however,  to  a  less  degree,  and  leads  to  a 
progressive  disintegration  of  the  protoplasm  on  the  side  towards 
the  anode,  which  lasts  until  the  current  is  again  broken.     (Figure 


■+-> 


Fig.  6. 

Actinosphaerium  eichhomii.     Four  stages  showing  the  progressive  influence 

of  a  constant  current.    Protoplasmic  disintegration  at 

the  side  toward  the  anode. 


6.)  Thus  even  though  there  can  be  no  doubt,  on  the  one  hand, 
that  the  effect  of  stimulation,  which  appears  at  the  moment  of 
the  entrance,  is  to  produce  alterations,  which  develop  very  rapidly, 
and  that  by  a  continuation  of  this  state  there  is  a  more  or  less 
rapid  fall  to  a  low  level ;  on  the  other  hand,  it  is  just  as  certain 
that  the  alterations  in  the  living  system  persist  throughout  the 
duration  of  the  changed  external  conditions,  or  to  put  it  more 


THE  CHARACTERISTICS  OE  STIMULI  59 

concisely :  the  effect  of  the  stimulus  never  wholly  disappears 
unless  the  changes  in  the  external  vital  conditions  return  to  their 
original  state. 

But  more,  an  effect  of  the  stimulus  cannot  indeed  take  place 
without  a  certain  duration  of  stimulation,  which  i.^  related  in  its 
turn  to  the  rapidity  of  reaction  of  particular  living  system.  This 
can  be  much  more  readily  observed  in  more  slowly  reacting  sub- 
stances. Fick'^  first  proved  this  fact  on  the  muscle  of  the  Ano- 
donta.  I  have  also  been  able  to  demonstrate  the  same  fact  in  the 
slowly  reacting  sea  rhizopods-  by  the  use  of  the  constant  current. 
When  Orbitolitcs  is  stimulated  with  a  constant  current  lasting 
approximately  the  tenth  of  a  second,  no  response  is  seen  in  its 
extended  pseudopods,  which  are  directed  towards  the  poles. 
The  same  is  the  case  if  the  induction  current  is  emi)loyed.  Only 
when  the  constant  current  of  the  uniform  strength  lasts 
approximately  .05  seconds,  a  barely  perceptible  response  occurs, 
manifested  by  the  sudden  stoppage  of  the  centrifugal  flowing  of 
granules  in  the  anodic  pseudopods,  which,  however,  after  the 
lapse  of  one  to  three  seconds  continues  again  unaltered.  Should 
the  duration  of  the  constant  current  be  still  further  prolonged, 
typical  symptoms  of  contraction  are  seen  being  manifested  by  a 
heaping  up  of  the  protoplasm  in  the  pseudopods  in  the  form  of 
spindles  and  balls,  whilst  the  protoplasm  flows  in  a  centrij)etal 
direction  towards  the  central  cell  body.     (Eigure  T.) 

Two  effects  can  be  realized  by  the  alteration  in  the  living 
system  as  the  result  of  prolonged  stimulation,  bjlher  a  new 
state  of  equilibrium  is  established  by  the  prolonged  action,  or 
sooner  or  later  death  develops.  In  considering  both  results,  huw- 
ever,  we  will  ignore  for  the  present  the  fact  that  every  living 
system  in  the  absence  of  such  prolonged  stimulation  is  always  in 
a  state  of  change,  i.e.,  development.  Only  with  this  restriction 
can  an  equilibrum  of  the  living  system  be  spoken  of. 

\  A.    Pick:    "Beitrage    zur    vcrgleichenden    Physiologic    der    irritablcn    Substanzcn." 

Braunschweig   1863. 

The  same:    "Untersuchungen    uber   die    electrische    Nervenrcizung."      Braunschweig 

1864. 

2  Max    Verworn:  "Untersuchungen  iiber   die  polare    Errcgung   dcr   Icbcndigcn    Sub- 

stanz,"  etc.     Ill  Pfliigers  Arch.  Bd.  62,   1896. 


e 
t 

3 
U 

PQ      ^ 

s 

(A 

e 

8 


c 
I 


03 

o 

BO    a 

3 

6 


I 

OQ 
I 

8 
I 


•S 


=— ^  < 


THE  CHARACTERISTICS  OF  STIMULI  61 

It  is  sometimes  the  case  that  under  the  iiitluence  of  a  stimulus 
a  new  equiHbrium  is  developed,  uhicii  may  remain  as  long  as 
the  stimulus  persists.  This  most  frccjuently  occurs  as  a  result 
of  weak  stimuli.  That  which  is  usually  termed  "individual 
adaptation"  belongs  in  this  category.  Likewise  some  of  the  nat- 
ural and  artificial  immunizations  may  also  be  included.  The  con- 
tinued stimulation  in  such  cases  of  adajjtation  as  we  learned 
before  in  the  example  of  Ama:ha  Umax  and  radiosa  or  liranchipiis 
stagnalis  and  Artcmia  salina  becomes  a  vital  condition  for  the 
living  substance  in  its  new  state. 

The  other  result,  namely,  that  of  death  ensuing  sooner  or 
later,  is  most  frequently  produced  by  stronger  stimulation. 
Through  the  effect  of  the  prolonged  stimulation,  the  change  in 
the  living  system  is  so  great  that  all  harmonious  interaction  of 
the  various  processes  of  life  become  after  a  time  impossible. 
The  disturbance  of  this  equilibrium  after  a  longer  or  shorter  time 
becomes  so  great  that  life  ceases.  By  far  the  greater  number  of 
all  diseases  furnish  examples  of  this  kind.  Disease  is  nothing 
else  but  reaction  to  stimulation.  Should  a  constant  stimulus  per- 
sist and  if  the  development  of  a  new  equilibrium  of  this  system 
is  not  established,  the  result  is  premature  death. 

In  most  cases,  as,  for  instance,  the  nerve  impulses  which  move 
toward  an  organ,  or  better  still  the  electrical  stinuili  as  used  for 
experimental  purposes,  it  is  not  a  question  of  a  i)ermanent  but 
of  a  temporary  alteration  in  the  external  vital  conditions.  The 
stimulus  starts,  then  ceases  after  a  longer  or  shorter  period.  In 
this  way  there  is  added  to  the  deviation  at  the  start  also  the  altera- 
tion at  its  termination.  The  latter  takes  place  with  difTcrent 
degrees  of  rapidity,  in  a  manner  analogous  to  that  of  the  initial 
alteration,  and  can  bring  about  response.  With  this  the  curve 
of  the  duration  of  the  course  of  the  stinuilus  becomes  somewhat 
more  complicated  and  in  consequence  a  like  effect  is  observed  in 
the  response.  The  "making,"  duration  and  "breaking"  of  the 
constant  current  furnishes  the  example  of  this  type.  The 
"making"  of  the  current  being  a  (|uick  alteration  calls  forth  a 
strong  and  sudden  excitation  (in  the  muscle  contraction)  :  the 
continuation  of  the  current  maintains  weak  excitation  of  ccjual 


62  IRRITABILITY 

intensity  (in  the  muscle  a  continued  contraction)  and  the 
"breaking,"  being  a  sudden  alteration,  is  followed  again  by  a 
stronger  excitation  (in  the  muscle  a  contraction).  The  duration 
of  the  change  can,  however,  be  so  short  that  its  intensity  does 
not  remain  at  two  periods  of  time  at  the  same  height,  but  instead 
the  ascent  of  the  intensity  is  immediately  followed  by  its  descent 
to  zero.  Induction  shocks  of  short  duration,  the  duration  of 
which  have  been  observed  more  in  detail  especially  by  Griitzner,^ 
offer  typical  examples.  Here  a  single  effect  of  the  stimulus  results 
from  the  rise  and  fall  of  the  intensity  curve.  Hence  the  induction 
shocks  as  momentary  stimuli  are  universally  used  for  experi- 
mental purposes. 

In  contrast  to  the  single  stimuli,  which  find  their  ideal  in 
induction  shocks,  another  form  of  stimulation  should  receive  our 
attention,  namely,  the  series  of  stimuli  which  produce  a  rhyth- 
mical alteration  of  vital  conditions.  These  show  among  their 
complex  combination  of  simultaneous  and  successive  actions  of 
their  single  stimuli  relatively  the  simplest  and  most  easily  under- 
stood regularity  in  their  effects.  They  are  of  particular  interest, 
because  they  develop  in  the  normal  physiological  happenings  of 
the  animal  body  in  the  form  of  rhythmical  intermittent  impulses 
of  the  nervous  system. 

Here  again  it  is  self-evident  that  with  regard  to  the  course  of 
response,  we  must  first  consider  the  character  of  the  single 
stimulus  of  the  series,  and  this  must  be  done  from  all  those  stand- 
points already  here  discussed.  However,  a  new  factor  is  met 
with  here,  that  is,  the  frequency  of  the  single  stimuli  of  the  series, 
or  that  which  has  the  same  meaning,  the  duration  of  the  intervals 
between  them.  This  is  a  feature  upon  which  the  result  of  stimu- 
lation depends  in  a  very  high  degree.  But  here,  too,  however, 
it  is  not  a  case  of  the  absolute  frequency  of  the  single  stimulus, 
but  simply  of  the  relative  frequency  in  regard  to  the  rapidity  of 
reaction  of  the  particular  living  system.  I  should  like  to  remark 
here  that  it  is  of  greatest  importance  whether  the  interval  between 
the  two  single  stimuli  of  the  series  is  sufficiently  long  or  not  to 

1  Grutzner:   "Uber   die    Reizwirkungen   der    Stohrer'schen    Maschine   auf  Nerv   und 
Muskel."     Pfliigers  Arch.   Bd.  41,   1887. 


THE  CHARACTERISTICS  OF  STIMULI  63 

allow  the  living  system  time  to  completely  recover  from  the  cfTect 
of  the  preceding  stimulus.  In  the  cases,  for  instance,  where  we 
have  recovery,  we  have  the  same  rhythm  of  stinuilation  as  that 
of  response.  When  recovery  does  not  occur,  interferences  of  the 
response  are  developed,  which  are  of  great  physiological  impor- 
tance, with  the  analysis  of  which  we  shall  later  on  lind  occasion 
to  occupy  ourselves  in  detail.  The  physiological  example  for  these 
stimuli  is  the  rhythmical  discharge  of  impulses  of  the  nerve 
centers;  the  physical  method,  which  is  most  widely  used  for 
experiments,  is  the  faradic  current. 

It  is  apparent  that  the  question  of  frequency  must  again  he 
combined  with  all  those  factors  previously  discussed  in  connec- 
tion with  the  single  stimulus.  In  consequence  another  compli- 
cation arises  and  with  this  another  point  must  be  taken  into 
consideration,  namely,  the  fact  that  the  duration  of  the  single 
stimulus  in  a  series  undergoes  alteration  by  increasing  frecjuency 
beyond  a  certain  limit.  Beyond  this  limit  the  duration  of  the 
single  stimulus  must  become  less  and  less.  As  the  result  of  the 
fact  that  stimulation  is,  as  we  have  seen,  dependent  on  the  dura- 
tion of  stimulus,  it  is  evident  that,  depending  upon  the  rai)idity 
of  response  of  the  living  system,  sooner  or  later  the  rhytlimical 
stimulation  must  become  ineflfectual.  Nevertheless,  this  effect 
of  shortening  the  duration  of  the  single  stimulus  can  be  compen- 
sated by  a  corresponding  increase  of  its  intensity.  In  this  con- 
nection Nernst^  showed  a  very  simple  relation  for  induction  cur- 
rents of  higher  frequency  of  interruption,  which  furnishes  a  law 
according  to  which  such  a  compensation  takes  place.  In  conjunc- 
tion with  Barratt  he  found,  namely,  that  the  intensity  must  in- 
crease proportionately  to  the  square  root  of  the  number  of  single 
stimuli  if  the  threshold  value  of  the  stimulus  is  to  be  maintained, 
that  is,  I:  V^^i  =  const.,  in  which  /  is  the  intensity  of  the  current 
and  m  the  frequency  of  interruptions.  The  limits  of  the  validity 
of  this  law  cannot  at  present  be  conclusively  established. 

This  exhausts  the  small  numl)er  of  elementary  factors  con- 
cerned in  the  course  of  the  stimulation,  and  which  are  of  imi)or- 

1  Nernst  und  Barratt:  "Uel)er  electrische  Nervenreizung  diirch  Wcchsclstromc." 
Zeitschrift  fur  Electrochemie   1904. 


64  IRRITABILITY 

tance  in  considering  its  effect.  The  combination  of  the  different 
varieties  of  these  single  factors,  that  is,  the  nature,  the  direction, 
the  intensity,  the  rapidity,  the  duration  and  number  of  altera- 
tions in  the  external  vital  conditions  of  the  organism  produce 
the  enormous  variety  of  effects  of  stimulation  which  we  observe 
in  the  living  world. 


CHAPTER   IV 

THE  GENERAL  EFFECT  OF  STIMULATION 

Contents:  Various  examples  of  the  effects  of  stimulation.  Metabolism 
of  rest  and  metabolism  of  stimulation.  Metabolic  equilibrium.  Dis- 
turbances of  equilibrium  by  stimuli.  Quantitative  and  qualitative 
alterations  of  the  metabolism  of  rest  under  the  influence  of  stimuli. 
Excitation  and  depression.  Specific  energy  of  living  substance. 
Qualitative  alterations  of  the  specific  metabolism  and  their  relations 
to  pathology.  Functional  and  cytoplastic  stimuli.  Relations  of  the 
cytoplastic  effects  of  stimuli  to  the  functional.  Hypertrophy  of 
activity  and  atrophy  of  inactivity.  Metabolic  alterations  during 
growth  of  the  cell.  Primary  and  secondary  effects  of  stimulation. 
Scheme  of  effects  of  stimulation. 

In  the  foregoing  lectures  we  have  had  occasion  to  touch  more 
or  less  often  on  the  subject  of  the  effects  of  the  stimuli.  This 
was  the  case,  however,  only  when  it  appeared  necessary  to  obtain 
a  systeinatic  knowledge  of  the  stimuli  and  the  differentiation  of 
the  individual  factors.  We  will  now  proceed  to  consider  the 
effect  of  stimulation  in  a  more  systematic  manner.  The  condi- 
tional method  of  observation,  however,  will  remain  our  guide. 

We  have  already  pointed  out  the  relations  between  the  con- 
ception of  stimulation  and  that  of  vital  conditions,  now  we  will 
consider  that  of  the  effect  of  stimulation  with  that  of  vital  pro- 
cesses. Nevertheless,  the  effect  of  stimulation  being  a  manifesta- 
tion of  the  vital  process  is  not,  therefore,  in  opposition  to  the  latter 
as  such.  Hence  the  question  presents  itself  as  to  the  connections 
between  vital  process  and  the  effect  of  stimulation. 

When  we  study  the  motile  flagellate  infusoriiun  Penuirma 
swimming  undisturbed  in  water,  we  observe  that  the  swimming 
movements  are  absolutely  regular  in  character.  The  elongated 
cell  body  remains  unaltered  in  shape.  The  long  flagellum  is 
extended  in  a  perfectly  straight  line  in  the  a.xis  of  the  Ix^ly  and 


66 


IRRITABILITY 


only  the  extreme  end  lashes  with  regularity  through  the  water 
(Figure  8,  A).  There  is  majestic  grace  in  this  perfect  uniformity 
of  motion.  The  picture  suddenly  alters  the  moment  the  Peranema 
is  influenced  by  the  slightest  jar.  The  whole  flagellum  at  once 
executes  a  few  violent  movements  (Figure  8,  B),  the  body  draws 
together,  soon  stretches  itself  again  and  swims  immediately  after, 
in  another  direction,  with  the  same  majestic  calm  as  before. 


\ 


Fig.  8. 

Peranema.    A— Swimming  in  non-stimulated  condition. 
B— Mechanically  stimulated  at  the  end  of  the  flagellum. 


Another  instance.  A  number  of  fertilized  eggs  of  the  sea 
urchin  are  placed  in  a  watch  glass  in  sea  water.  The  temperature 
of  the  water  should  correspond  with  the  mean  temperature  in 
which  the  animals  live  in  the  sea,  averaging  about  15°  C.  The 
eggs  begin  to  form  grooves  and  to  develop  slowly  by  progressive 
division.  In  another  glass  we  observe  a  second  sample  of  fer- 
tilized eggs  of  the  same  kind  and  under  the  same  conditions,  but 
in  this  case  we  increase  the  temperature  to  25°  C.  The  increased 
temperature  brings  about  a  decided  increase  of  segmentation  and 
the  same  stage  of  development  is  reached  in  less  than  half  the 
time.  The  increased  temperature,  therefore,  increases  the  devel- 
opment. Further  we  take  a  third  sample  of  the  same  urchin 
eggs  in  a  watch  glass  with  sea  water  of  15°  C.  and  add  a  little 


THE  GENERAL  EFFECT  OF  STIMULATION       67 

sea  water  mixed  with  ether.  The  development  of  the  eggs  now 
comes  to  a  standstill.  The  narcotic  has  produced  an  inhibition 
of  development. 

To  quote  another  instance.  Bacterium  phosphorcscn^s  having 
been  bred  upon  a  putrid  hsh  are  ex|)osed  in  the  culture  thiid  lo 
the  air.  In  the  dark  the  bacteria  give  forth  a  |)hosphoresccnl 
light.  Then  the  culture  fluid  containing  the  bacteria  i>  i)ut  into 
a  glass  receptacle,  which  can  be  rendered  air-tight  and  all  oxygen 
excluded.  After  a  short  time  the  light  formation  ceases  com- 
pletely. The  absence  of  oxygen  has  here  had  a  depressing  effect 
and  it  is  only  after  air  has  been  again  introduced  that  light  is  once 
more  produced. 

Lastly,  an  example  from  the  group  of  mammals  may  be  cited. 
The  metabolism  of  a  dog  in  comi)lete  rest  is  examined  for  a  pro- 
longed length  of  time  and  we  ascertain  the  values  of  the  oxygen 
consumption,  the  carbon  dioxide  production,  and  the  nitrogen 
elimination  in  the  urine.  Under  the  same  nutritive  conditions 
the  animal  is  then  allowed  to  work  from  time  to  time  in  a  tread- 
mill. During  these  working  periods  impulses  of  excitation  are 
continually  conducted  to  the  muscles  from  the  nervous  system. 
It  is  now  found  that  under  the  influence  of  the  constantly  re- 
curring stimuli  the  quantity  of  nitrogen  in  the  urine  has  only 
very  slightly  augmented,  whereas  the  consumption  of  oxygen  and 
the  production  of  carbon  dioxide  has  markedly  increased. 

What  conclusions  can  be  drawn  from  these  instances  of  re- 
sponse to  stimuli,  of  which  any  number  could  still  be  quoted? 
They  show  us,  first  of  all,  that  a  state  or  process  existing  under 
given  conditions,  is  altered  by  the  influence  of  the  stinuilus.  This 
is  a  fact,  however,  which  could  be  expected  from  the  beginning 
and  is  self-evident,  for  stimuli  are  alterations  in  the  vital  condi- 
tions, and  when  these  are  altered  the  state  of  the  system  or  the 
happenings  thereof  must  also  alter.  The  cjuestion  with  which 
we  are  here  more  closely  concerned,  however,  is  a  somewhat 
more  detailed  characterization  of  the  state  or  process  itself,  as 
well  as  that  of  alterations  produced  by  the  influence  of  the  stimu- 
lus. The  instances  of  resi)onse  to  stimuli  already  cite<l  furnish 
us  with  information  in  both  kinds. 


68  IRRITABILITY 

In  all  these  examples,  the  living  processes  occur  with  equal 
constancy  and  unaltered  rapidity,  provided  a  stimulus  is  not 
operative.  Here,  however,  the  gradual  alterations,  the  result  of 
development,  must  not  be  overlooked.  An  excellent  example  of 
this  is  seen  in  the  eggs  of  sea  urchin,  where  the  development  is 
readily  perceptible.  In  all  these  instances,  however,  the  condi- 
tion is  immediately  changed  by  the  influence  of  the  stimulus. 
The  previous  state  of  constancy  in  the  vital  process  is  disturbed. 
The  rapidity  of  its  course  is  changed,  being  either  increased  or 
decreased,  and  the  specific  vital  manifestations  concerned  are, 
therefore,  augmented  or  diminished.  We  will  now  study  the 
vital  process  with  the  methods  of  chemical  investigation  and  con- 
sider the  problem  from  the  standpoint  of  metabolism.  It  may 
be  noted  here,  that  other  methods,  such  as  the  transformation  of 
energy  or  changes  of  form  of  the  living  system,  would  serve 
equally  well  as  indicators  for  this  purpose.  In  every  instance 
there  is  a  uniformity  of  the  processes;  the  difference,  however, 
is  in  the  nature  of  the  indicators  and  the  terms  used.  The  meth- 
ods and  the  terms  used  in  chemical  investigation  and  description 
reach  proportionately  much  deeper  than  those  employed  when 
the  transformation,  energy  or  the  variations  of  form  of  the 
organisms  are  studied,  and  permit  of  the  finest  difi:erentiation  of 
the  processes.  The  atomistic  terminology  is,  for  this  reason, 
preeminently  fitted  for  the  description  of  vital  processes.  When 
we  study  the  vital  process  metabolically,  we  can,  as  shown  in  the 
above-mentioned  instance,  divide  the  processes  into  a  metabolism 
of  stimulation  in  contradistinction  to  a  metabolism  of  rest. 

The  comprehension  of  the  metabolism  of  rest  demands  a  closer 
consideration.  On  closer  observation  we  must  say  that  this 
much-used  conception  is  merely  an  abstraction  nowhere  realized 
in  a  strict  sense.  In  truth,  there  is  nowhere  in  nature  a  metab- 
olism of  rest.  No  cell  exists  which  in  a  mathematical  sense 
remains  for  even  two  successive  moments  under  absolutely  the 
same  external  conditions.  If  we  imagine  a  single  living  cell  of 
the  simplest  kind  living  in  a  fluid  nutritive  medium,  and  if  we 
suppose  its  body  and  surroundings  so  magnified  that  the  single 
molecules  and  atoms  were  respectively  of  the  size  of  cannon  and 


THE  GENERAL  EFFECT  OF  STIMULATION       69 

rifle  balls,  the  boundary  between  cell  and  medium  would  repre- 
sent a  battlefield,  on  which  a  heavy  bombardment  is  constantly 
taking  place.  The  rain  of  shot  of  food  and  oxygen  molecules 
penetrating  into  the  cell  from  the  medium,  would  produce  an 
explosion  in  the  existing  ammunition  depots,  now  at  one  point, 
now  at  another,  creating  great  breaches  through  which  new 
masses  of  shot  w^ould  reach  the  interior.  The  fragments  of  these 
exploding  molecules  would  be  flung  out  here  and  there  into  the 
medium  and  would  stem,  now  at  this,  now  at  that  point  the 
besieging  masses  of  shot.  In  this  wild  confusion  on  the  whole 
boundary  line  between  cell  and  medium  there  can  be  no  question 
of  rest  or  even  equilibrium  at  any  point.  The  human  mind, 
superior  to  the  material  world  as  we  may  deem  it,  is  yet  always 
dependent  upon  the  results  of  experience,  and  even  in  its  highest 
flights  cannot  become  wholly  emancipated  from  the  concrete 
objects.  For  this  reason  it  is  of  great  purport  to  conceive  pro- 
cesses whose  dimensions  cannot  be  observed  even  microscopically, 
as  enlarged  and  transformed  to  that  method  of  expression  most 
familiar  to  the  human  mind,  namely,  in  the  field  of  optical  pre- 
sentation. This  method  is  of  great  help  in  aiding  our  under- 
standing, and  likewise  here,  even  in  the  resting  state,  the  cell  is 
constantly  exposed  to  local  effects  of  stimulation,  now  at  one 
point,  now  at  the  other.  The  conception  of  the  metabolism  of 
rest  is,  therefore,  in  a  strict  sense  fiction. 

Nevertheless,  the  conception  of  the  metabolism  of  rest  as  an 
abstraction  can  be  of  value  provided  always  that  it  is  strictly 
and  definitely  limited.  It  must,  for  instance,  not  be  applied  to 
short  periods  of  time.  The  continued  local  and  temporary  re- 
sponses to  stimulation  constitute  a  mean  value  which,  although 
composed  of  numberless  small  sub-threshold  responses,  we  can 
still  call  a  metabolism  of  rest.  Weak  stimuli  have,  liowever,  as 
already  seen,  the  property,  provided  their  influence  is  constant, 
of  effecting  an  adaptation  to  the  stimulus  on  the  part  of  the  living 
organism,  so  that  the  stimulus  becomes  a  vital  condition  for  this 
state  of  the  organism.  Hence  the  continued  existence  of  a  vital 
process  resulting  from  the  constant  action  of  slinuilation  is  made 
possible.     That  which  we  are  in  the  habit  of  calling  metabolism 


70  IRRITABILITY 

of  rest,  would,  therefore,  be  metabolism  of  stimulation,  but  one 
that  is  characterized  by  a  constantly  existing  metabolic  equilib- 
rium. 

This  "equilibrium  of  metabolism"  distinguishes  the  metabolism 
of  rest  from  that  form  which  is  developed  in  response  to  tem- 
porary stimulation,  in  that  every  temporary  stimulation  has  the 
effect  that  it  disturbs  the  existing  metabolic  equilibrium  for  a 
longer  or  shorter  time.  This  disturbance  of  the  equilibrium  of 
metabolism  can  in  contrast  to  the  metabolism  of  rest  be  termed 
''metabolism  of  stimulation."  In  this,  but  only  in  this  sense,  can 
these  two  conceptions  be  placed  in  opposition  and  used  to  char- 
acterize the  processes  in  the  living  organism.  The  conception 
of  the  metabolism  of  stimulation  must  always  stand  in  relation 
to  that  of  an  equilibrium  of  metabolism  characterized  by  a  con- 
stantly existing  metabolism  of  rest,  just  as  the  conception  of 
stimulus  can  likewise  only  be  defined  relatively  to  that  of  vital 
conditions. 

Nevertheless,  the  conception  of  the  equilibrium  of  metabolism 
requires  a  somewhat  more  accurate  definition  before  we  can  feel 
justified  in  using  this  term.  Definitions  are  always  trite,  never- 
theless they  are  the  basis  of  all  our  thinking  and  a  definite  under- 
standing is  impossible  unless  we  first  clearly  fix  their  contents. 
The  history  of  theology  and  philosophy  even  to  the  most  recent 
times  furnishes  a  long  line  of  instances  in  which  the  most  eminent 
minds,  for  the  want  of  fixed  definitions  of  the  conceptions  which 
they  made  use  of,  failed  to  find  a  mutual  basis  for  their  ideas. 
Without  a  sharp  definition  every  conception  is  a  mere  word, 
which  each  individual,  according  to  his  personal  experiences  and 
views,  endows  with  a  different  meaning.  To  such  conceptions 
we  may  apply  Mephisto's  ironical  comment  to  his  pupil : 

"  Mit  Worten  lasst  sich  trefflich  streiten, 
Mit  Worten  ein  System  bereiten." 

The  natural  sciences,  if  they  are  to  retain  their  reputation  for 
exactness  and  precision,  require  the  strictest  and  clearest  defini- 
tions of  all  conceptions.  If  we  seek  to  penetrate  more  deeply 
into  the  varied  happenings  in  concrete  conditions,  we  must  recon- 


THE  GENERAL  EFFECT  OF  STIMULATIOX        71 

cile  ourselves  to  dry  pedantic  definitions.  In  the  case  of  tliat 
of  the  equilibrium  of  metabolism  indeed  we  liave  before  us  one 
of  the  most  important  conceptions  in  ])hysiology. 

The  justification  to  speak  of  an  c(|uilil)rium  of  metabolism 
arises  from  investigations  of  metabolism  in  mammals.  The  clas- 
sical experiments  of  the  previous  century,  as  is  well  known,  have 
shown  that  in  the  adult  mammal  receiving  a  necessary  quantitv 
of  nourishment  and  in  a  state  of  rest,  the  intake  and  outgo  of 
the  constituent  elements  are  the  same.  The  carbon,  iiydrogen, 
nitrogen,  oxygen,  sulphur,  phosphorus,  etc.,  taken  in  during 
a  lengthened  period  in  the  form  of  food  and  resi)ired  air. 
appear  again  in  equal  quantity,  in  other  combinations,  in  the 
products  of  excretion  of  the  organisms.  Calorimetric  exi)eriments 
likewise  show  an  equilibrium  of  the  consumption  and  elimination 
of  energy.  If  there  thus  exists  an  equilibrium  of  metabolism  for 
the  whole  cell  community,  it  is  clear  that  the  same  must  also  api)ly 
to  the  individual  cell,  that  is,  for  all  living  substance.  The  quan- 
titative relations  of  the  foodstufTs  taken  /;/.  and  the  excreted  meta- 
bolic products  given  off,  are,  however,  merely  a  standard  of  the 
metabolism.  We  know  that  the  former  are  used  to  build  up  new 
living  substance  and  that  the  latter  represent  the  result  of  dis- 
integration of  that  previously  existing  living  substance ;  for  we 
find,  as  in  the  case  of  the  plant,  complicated  protein  combinations, 
which  are  built  up  from  comparatively  simple  constituents  of  the 
food  and  are  again  broken  down  into  comparatively  simple  sub- 
stances. And  so  the  building  up  and  breaking  down  ])rocesses 
form  the  two  great  processes  of  metabolism,  which  with  llcrimf 
we  can  briefly  call  ''assimilation"  and  "iiissimilation."  In  the 
terms  assimilation  and  dissimilation  are  comprised  the  sum  of  all 
processes  of  construction  and  disintegration  in  the  living  organ- 
ism. It  is  apparent  that  equilibrium  of  metabolism  occurs  when 
assimilation  and  dissimilation  are  equal.  The  formula  .X  :  D.  that 
is,  the  relation  of  the  sum  of  all  assimilation  to  the  sum  of  that  of 
all  dissimilative  processes,  is  a  factor  of  fundamental  importance 
in  the  study  of  the  course  of  the  vital  i)rocesses,  for  u\kh\  its 

1  E.  Hcring:  "Zur  Theorie  der  Vorgange  in  dcr  Icbendigcn  Siihstanz."  In  Lotos. 
Bd.  9,   Prag.    1888. 


72  IRRITABILITY 

value  depends  individual  vital  manifestation,  and,  in  fact,  the  con- 
tinuation of  life.  I  have,  therefore,  designated  the  formula 
A  =  D  ''Biotonus."  The  equilibrium  of  metabolism  would  then 
be  characterized  by  the  biotonus^  of  a  living  organism  being 
equal  to  one.  This  would  be  the  metabolism  of  rest  of  a  system, 
whilst  its  metabolism  of  stimulation  would  consist  in  an  altera- 
tion of  the  biotonus.  But  is  this  state  of  living  substance  strictly 
speaking  ever  realized? 

In  considering  the  nature  of  the  equilibrium  of  metabolism 
one  factor  has  been  disregarded  which  must  be  taken  into  ac- 
count at  every  point;  this  is  growth.  Growth  changes,  although 
varying  more  or  less,  are  never  absent  during  the  life  of  the 
organism.  An  equilibrium  of  metabolism  never  exists  in  a 
strictly  mathematical  sense,  and  here  again  we  are  working  with 
a  conception  which  is  faulty,  because  it  is  an  abstraction,  origi- 
nating from  experience  with  rather  too  restricted  boundaries. 
But  an  error  of  which  one  is  aware  is  not  dangerous.  In  mathe- 
matics we  also  consciously  reckon  with  errors,  without  the  result 
being  altered.  In  the  before  mentioned  cases  the  equilibrium  of 
metabolism  was  maintained,  because  the  investigations  involved 
only  a  short  time  in  an  adult  mammal.  In  the  adult  mammal  the 
growth  processes  occur  very  slowly,  so  that  alterations  within 
a  relatively  short  time  are  not  demonstrated. 

If  it  were  possible  to  subject  the  adult  mammal  to  metabolic 
or  calorimetric  experiments,  extending  for  years,  it  would  be 
found  that  the  intake  would  be  qualitatively  and  quantitatively 
different  at  the  end  of  the  investigation  and  that  the  same  would 
apply  to  the  outgo.  In  the  growing  tgg  cell  this  takes  place  with 
much  more  rapidity.  In  the  organism  which  rapidly  grows,  it 
can  be  seen  at  once  that  the  quantity  of  the  outgo  of  the  products 
of  disintegration  cannot  be  equal  to  that  of  the  intake  of  food- 
stuffs. If  biotonus  were  equal  to  one,  the  organism  could  not 
grow.  Equilibrium  of  metabolism  can  only  be  understood  when 
we  take  into  consideration  a  period  of  time  in  which  the  altera- 
tions in  growth  take  place  with  such  imperceptible  slowness  that 

1  Max  Verworn:  "Allgemeine  Physiologic.  Ein  Grundriss  der  Lehre  vom  Leben." 
V.  Aufl.  Jena  1909. 


THE  GENERAL  EFFECT  OF  STIMTLATIOX       73 

the  resultant  error  is  inconsiderably  minute.  This  period  of  time 
is  of  greatly  varying  length  in  different  living  organisms  and  tiiis 
fact  must  be  taken  into  account  in  every  living  form.  ( )nly  witli 
this  restriction  can  we  justify  the  use  of  the  term  "e(iuilibrium 
of  metabolism."     Then,  however,  its  use  is  of  great  value. 

The  metabolism  of  stimulation  is  then  a  disturbance  of  the 
metabolism  of  rest,  that  is,  a  disturbance  of  the  ccjuilibrium  of 
metabolism  through  the  effect  of  stimuli. 

The  question  here  follows:  Is  there  a  constancy  of  this  inter- 
ruption of  the  equilibrium  of  rest  produced  by  the  stimulus  whicli 
can  be  formulated  into  a  general  law?  To  begin  with,  the  number 
of  possible  responses  are  greater  than  the  variety  of  forms  of 
living  substance,  for  every  living  organism  with  its  specific  proj)- 
erties  can  undergo  alteration  in  its  metabolism  in  various  direc- 
tions. Thereby  results  an  infinite  number  of  manifold  reactions 
to  stimuli.  However,  in  answer  to  the  question,  in  which  direc- 
tion the  change  in  the  specific  metabolism  of  rest  in  response  to  a 
stimulus  takes  place,  we  find  a  comparatively  simple  scheme  of 
general  reaction.  All  phenomena  can  change  in  their  rai)idity  as 
well  as  in  their  nature.  That  is  quantitatively  and  qualitatively. 
In  this  way  the  specific  vital  process  of  an  organism  can  be  altered 
by  the  stimulus,  on  the  one  hand,  in  its  rai)idity :  on  the  otiier.  in 
the  manner  of  its  action. 

The  majority  of  all  temporary  responses  to  stimuli  consist  in 
alterations  of  rapidity  of  the  vital  process,  and  form  either  a 
quickening  or  retardation  of  its  course.  The  former  is  mani- 
fested in  a  strengthening  or  an  increase,  the  latter  in  a  decrease 
or  repression  of  the  specific  action  of  the  living  organism.  The 
stimuli  have  the  same  effect  as  in  the  case  of  the  catalysers  in 
chemical  processes.  According  to  Ostzcald's^  well-known  defi- 
nition of  catalysis  a  catalyser  is  a  substance  which,  without 
appearing  in  the  final  product  of  a  chemical  reaction,  alters  its 
rapidity.  This  group  of  reactions  can,  therefore,  be  referred  to 
as  "catalytic  stimulation  and  response."  When  the  response 
consists  in  increase,   we  speak,   in  a  physiological   sense,  of  an 

1  Ostzvald:  "Ueber  Katalyse."     Verhandl.  d.  Ges.   Dcutschcr  Naturf.  und  Acrzle  zu 

Hamburg  1901. 


U  IRRITABILITY 

excitation,  and  when  there  is  decrease  in  the  vital  processes,  we 
speak  of  a  depression. 

The  conception  of  excitation  and  depression  are  purely  empiri- 
cal. They  are  terms  for  real  things,  referring,  in  fact,  simply  to 
alterations  in  rapidity  of  life  process,  which  can  be  as  readily 
observed  as  the  process  itself.  I  wish  to  lay  particular  stress  on 
this  fact,  for  the  reason  that  Cremer'^  has  recently  made  the 
extraordinary  statement  that  I  have  introduced  hypothetical  pro- 
cesses into  the  definition  of  the  conception  of  excitation.  I  have 
always  considered  excitation  as  merely  an  increase  or  change  of 
intensity  of  the  specific  actions  of  a  living  system,  and  as  such  is 
an  established  process  without  a  trace  of  the  hypothetical  element.^ 
If,  however,  the  excitation  process  is  to  be  regarded  as  something 
absolute,  as  a  mysterious  state  siii  generis,  which  is  entirely  inde- 
pendent and  totally  unlike  the  metabolism  of  rest,  then,  of  course, 
it  would  appear  utterly  incomprehensible  and  would  be  without 
purpose.  As  an  absolute  process  excitation  is  merely  a  meaning- 
less word.  Excitation  and  depression  are  relative  conceptions 
and  can  only  acquire  meaning  when  the  process  which  is  exci- 
tated  or  depressed  is  more  closely  defined.  This  is  the  specific 
vital  process  of  a  given  organism,  and  the  two  conceptions  only 
have  meaning  in  relation  to  it.  The  conception  of  the  vital  pro- 
cess, however,  is  one  directly  gained  from  experience.  However 
complex  or  difficult  to  analyze  the  process  may  be,  it  still  is  as 
little  hypothetical  as  that  of  the  combustion  of  carbon  into  carbon 
dioxide,  or  the  revolving  of  the  earth  around  the  sun.  It  can  be 
looked  upon  as  something  positive  and  real.  Quite  another 
question  is  the  manner  in  which  we  are  to  consider  the  mechanism 
of  the  vital  process.  In  analyzing  this  mechanism  we  cannot,  at 
least  in  the  present  state  of  our  knowledge,  entirely  dispense  with 
hypothesis.  But  these  hypotheses  are  in  no  way  involved  in  the 
definition  of  the  process  of  excitation.     If  we  look  upon  every 

1  Cremer:  "Die  allgemeine  Physiologic  der  Nerven."  In  Nagels  Handbuch  der 
Physiologic  des  Menschcn.     Bd.   IV,   Braunschweig  1909. 

2  In  the  first  edition  of  my  "General  Physiology"  in  1895  I  have  sharply  and  clearly 
defined  it  as  such,  stating  in  formulating  the  general  law  of  stimulation:  that  every 
excitation  is  an  increase  either  of  individual  parts  or  the  whole  of  vital  phenomena, 
depression  every  decrease  in  the  individual  part  or  the  whole  of  vital  phenomena. 


THE  GENERAL  EFFECT  OF  STIMULATION        73 

excitation  or  depression  produced  hy  a  stimulus  as  an  alteration 
in  rapidity  in  the  specific  vital  process  of  a  given  organism,  we 
are  thereby  expressing  the  same  fact  which  Johannes  Mullcr  has 
termed  ''specific  energy:'  We  give,  however,  the  doctrine  of 
specific  energy  a  more  general  applicali(;n  in  so  far  as  it  com- 
prehends not  only  the  increase  but  likewise  the  decrease  of  activity 
in  response  to  stimuli.  Johannes  Midler  s  doctrine  of  specific 
energy  of  the  living  substance  at  all  times  has  been  the  subject 
of  most  animated  discussion.  When  I  refer  here  h)  the  specific 
energy  of  living  substance,  it  is  with  the  knowledge  that  Johannes 
Midler  did  not  use  this  expression  of  "living  substance"  in  this 
connection.  He  was  already  acquainted,  however,  as  we  have 
seen,  with  the  fact  of  the  existence  of  the  specific  energy  of  all 
living  structures.  For  appertaining  to  the  muscle  he  says :  *This 
is  universal  in  all  organic  reaction."  The  reason  why  the  doc- 
trine of  sense  energy  has  become  of  importance  in  the  discussion 
of  the  specific  energy  of  the  living  substance,  is  in  consequence  of 
the  theoretical  interest,  resulting  from  its  connection  with  the 
nature  of  the  specific  energy  of  our  sense  substances.  The  con- 
troversies on  this  subject  are  still  far  from  settled.'  Indeed, 
according  to  the  special  philosophical  standpoint  taken  by  an 
observer,  the  existence  of  a  specific  energy  of  the  senses  is 
acknowledged  or  disputed.  For  any  one  acquainted  with  the 
general  physiological  reaction  to  stimuli,  such  a  discussion  is 
wholly  without  purport.  The  sense  substances  have  as  a  matter 
of  course  in  common  with  all  living  substances  their  specific 
energy,  that  is,  the  influence  of  stimuli  can  produce  an  increase 
or  decrease  of  their  specific  vital  processes.  "Specific  energy"  of 
"sense  substance"  in  this  sense  is  like  that  of  all  other  living  .sub- 
stances, a  fact.  In  that  the  psychical  ca])al)iliiy  of  these  sense 
substances,  in  which  we  include  not  only  the  peripheral,  i)ui  also 
the  central  portion,  are  dependent  upon  their  specific  vital  pro- 
cesses, it  must  be  self-evident  that  the  excitation  and  the  sup- 
pression of  sense  sensation  can  be  brought  about  by  adecjuate  and 

1   Compare:   Rudolf   Weinmann:  "Die   I.chre  von   den  spccifischcn   Sinncscncrgicn." 
Hamburg  1895. 

Further:   Eugen  Minkowski:  "Zur  Miillerschcn   I.ehre  von   den   specifischcn   Sinncs- 

energien."      In    Zeitschrift    f.    Sinn(.si)Iiysiolofiic.    Hd.    45.  1*>11. 


76  IRRITABILITY 

inadequate  stimuli,  no  matter  what  one  may  think  of  the  relations 
between  physical  and  psychical  phenomena. 

The  only  debatable  question  is  that  concerning  the  limits  of  the 
validity  of  the  doctrine  of  the  specific  energy  of  living  substances. 
This  question  will  involve  our  attention  when  we  have  analyzed 
somewhat  more  closely  the  happenings  in  the  living  substance 
taking  place  under  the  influence  of  stimuli.  We  will,  therefore, 
return  later  on  to  a  more  detailed  consideration  of  the  last  ques- 
tion. Nevertheless,  we  will  here  refer  to  a  fact  which,  upon  a 
superficial  observation,  seems  to  restrict  the  validity  of  the  con- 
ception of  the  specific  energy  of  living  substance. 

In  contrast  to  those  reactions  to  stimuli,  which  consist  merely 
in  the  changes  of  a  rapidity  of  the  specific  vital  process,  are 
another  group  of  reactions  in  which  the  influence  of  stimuli  leads 
to  qualitative  alterations  in  the  specific  vital  process.  In  these 
instances,  the  influence  of  the  stimulus  directs  the  metabolism  of 
rest  into  new  channels,  so  that  chemical  processes  occur  in  the 
cell,  which  under  ordinary  circumstances  do  not  take  place.  This 
group  of  reactions,  which  I  wish  to  term  "metamorphic  stimula- 
tion and  response,"  are  chiefly  observed  where  weak  stimuli  act 
continuously  upon  the  living  substance.  These  are  essentially 
weak  chemical  stimuli,  which  last  for  a  prolonged  period  or  fre- 
quently reoccur  in  the  life  of  the  cell  community.  Examples  of 
this  are  found  in  the  continual  ingestion  of  alcohol  and  other 
poisons  by  the  human  being,  or  in  the  formation  of  metabolic 
products  of  bacteria,  etc.  The  majority  of  chronic  diseases 
belong  to  this  group  of  reactions ;  disease  being  simply  response 
to  stimulation.  Disease  is  life  under  altered  vital  conditions  and 
altered  vital  conditions  are  stimuli.  This  simple  and  self-evident 
fact  shows  the  immense  importance  which  the  knowledge  of  the 
general  laws  of  the  physiology  of  stimulation  has  for  pathology. 
The  pathologist,  who  does  not  wish  to  confine  his  observations 
to  a  purely  superficial  symptomatology  or  a  merely  histological 
morphology,  must  seek  above  all  to  penetrate  as  deeply  as  possible 
into  the  nature  of  the  general  reactions  to  stimulation  in  the  living 
organism.  It  is  the  essential  point  which  meets  him  everywhere. 
In  spite  of  their  great  interest  for  pathology,  however,  it  is  just 


THE  GENERAL  EFFECT  OF  STIMULATION 


i  < 


these  qualitative  alterations  of  the  normal  vital  j)roccss  produced 
by  continuous  stimulation  which  have  up  to  now  hccn  least  ana- 
lyzed. In  this  field  we  expect  much  from  pathological  inves- 
tigation which  alone  has  the  immense  amount  of  material  at  its 
command.  This  will  take  i)lace  only  when  i)ath()lo^ry  adds  to  the 
almost  exclusively  histological  direction  of  investigation,  that  also 
of  experimental  physiology.  It  is  true  that  the  i)r()hlems  of  the 
qualitative  alterations  of  a  vital  process  by  chronic  stimulation 
are  much  more  complicated  than  those  of  the  rai)id  responses  to 
temporary  stimuli,  consisting  simply  in  mere  alterations  of 
rapidity  of  the  specific  vital  process.  An  understanding  of  the 
nature  of  the  former  can  only  be  expected  when  a  deei)er  knowl- 
edge of  the  latter  is  gained,  for,  as  will  be  seen  presently,  there  is 
the  closest  relation  between  the  two  groups. 

The  reactions  to  catalytic  stimuli  of  short  duration,  which  pro- 
duce merely  an  alteration  of  rapidity  in  the  specific  phenomena 
of  a  living  organism,  show  on  a  closer  analysis  the  interesting 
fact,  that  it  is  not  always  the  entire  metabolic  processes  of  the 
cell  which  are  perceptibly  quickened,  but  that  only  certain  con- 
stituent processes  of  the  same  are  afYected  by  the  action  of  exci- 
tation. This  is  the  more  noticeable,  as,  considering  the  close  corre- 
lation which  all  the  individual  links  of  the  chain  of  metabolism 
bear  to  each  other,  it  is  to  be  expected  that  the  alteration  in  rapid- 
ity of  one  would  be  followed  at  once  by  a  corresponding  change 
in  all  the  others.  An  example  of  the  case  in  question,  in  which 
a  special  constituent  process  may  be  predominately  atYected.  is 
that  of  the  specific  activity  of  a  muscle  which  is  rejieatedly  stimu- 
lated by  nervous  impulses.  Since  the  classical  investigation  of 
Fiek  and  IVislieenns^  on  themselves,  and  of  Voit'  on  the  dog.  we 
know  that  the  nitrogen  metabolism  is  practically  unaltered  by 
the  functional  use  of  the  muscle  and  there  is  a  remarkable 
increase  only  in  the  breaking  down  of  the  nitrogen- free  groups 

1  Pick  und  Wislicenus:  "Uebcr  die  Entstchung  der  Muskclkraft."  Vicrtcljahrc*- 
schrift  d.   Ziiricher   Naturforschenden   Gesellschaft.      Rd.    10,    1865. 

2  I'oit:  "Ueber  die  Entwicklung  dcr  I,clire  dcr  Quelle  dcr  Muskclkraft  luid  ciniger 
Theile  der  Ernahrung  scit  25  Jahrcn."     Zeitschrift  f.    BioloRic   Hd.   VI.  1870. 

Derselbe:  Physiologie  des  aligemcinen  StofTwcchscIs  u.  d.  Ernahrung.  In  Her- 
manns Handbuch  d.   Physiologie.   Bd.  VI,   1881. 


78  IRRITABILITY 

of  the  living  substance.  Sufficient  importance  has  not  as  yet  been 
attached  to  this  knowledge.  This  fact  not  only  has  a  particular 
interest  for  the  much-discussed  question  of  the  source  of  muscle 
energy,  but  also  affords  a  deeper  insight  into  the  metabolic  activity 
of  the  living  substance.  It  shows  us  that  we  must  not  imagine 
a  purely  linear  linking  of  the  individual  constituent  metabolic 
processes,  but  rather,  at  least  at  certain  points,  a  branching  forma- 
tion, the  individual  members  spreading  in  various  directions.  An 
alteration  in  an  individual  member  can  occur  without  an  imme- 
diate change  in  the  other  branches.  This  would  not  be  the  case 
if  there  were  only  a  linear  connection  of  the  constituent  processes, 
for  the  breaking  of  a  single  member  of  the  chain  would  be 
followed  by  a  change  in  all  the  following  members. 

It  shows  us,  further,  that  certain  branches  are  more  labile  than 
others.  In  the  case  referred  to  here,  the  branches  of  this  system, 
which  bring  about  the  nitrogen  metabolism,  are  relatively  firm 
and  stable,  the  branches,  which  are  disturbed  by  the  stimulus  pro- 
ducing functional  activity  of  the  muscle,  are  particularly  labile. 
I  should  like  in  passing  to  call  here  your  attention  to  the  fact  that 
as  is  well  known,  Ehrlich,'^  in  another  field  involving  other  condi- 
tions and  other  experiences  and  considerations,  has  arrived  in 
analogous  manner  at  his  "side  chain  theory."  In  order  to  have 
an  expression  for  those  stimuli  which  involve  rapid  alteration  of 
the  labile  constituent  processes  and  which  are  connected  with  the 
specific  action  of  the  particular  organism,  I  have  called  them 
''functional  stimuli,"  and  contrasted  with  them  the  "cytoplastic 
stimuli."  In  the  latter  the  alterations  produced  include  all  the 
constituent  processes  extending  even  to  the  stable  processes  of 
nitrogen  changes,  and  sometimes  extend  to  complete  disintegration 
and  rebuilding  of  living  substance.-  To  the  first  group  belong 
all  adequate  stimuli  within  certain  limits  of  duration  and  intensity, 
and  the  greater  part  of  inadequate  stimuli  of  brief  duration  so 

1  Ehrlich :  "Das  SauerstoiTbediirfniss  des  Organismus.  Eine  farbenanalytische 
Studie."  Berlin  1885.  Compare  further:  L.  Aschoff :  "Ehrlich's  Seitenkettentheorie 
und  ihre  Anwendung  auf  die  kiinstliche  Immunisirungsprocesse.  Zusammenfassende 
Darstellung."     Zeitschr.   f.  allgemeine  Physiologic,  Bd.   I,   1902. 

2  Max  Verworn:  "Die  Biogenhypothese.  Eine  kritisch-experimentelle  Studie  iiber 
die  Vorgange  in  der  lebendigen  Substanz."     Jena   1905. 


THE  GENERAL  EFFECT  OF  STIMULATION       79 

long  as  they  do  not  exceed  a  certain  intensity.  To  the  latter 
group  belong  in  general  all  the  stronger  adequate  and  inadequate 
stimuli  of  prolonged  duration;  such  as  extreme  temperature,  the 
stronger  electric  currents,  constant  alteration  in  the  sui)ply  of 
food,  water,  oxygen,  the  prolonged  or  stronger  influence  of 
extraneous  chemical  matter,  etc. 

Considering  the  close  correlation  of  the  individual  part  pro- 
cesses it  would  appear  very  strange,  however,  if  a  single  one  of 
these  could  undergo  an  alteration  of  its  rapidity  without  the 
course  of  the  rest  of  the  processes  being  in  the  least  influenced. 
One  cannot  comprehend  such  absolute  independence  of  a  process 
brought  about  by  functional  stimulation  from  all  the  other  con- 
stituent processes,  particularly  when  this  is  of  prolonged  duration 
and  involves  to  a  considerable  extent  the  alterations  in  rapiditv, 
for  the  individual  constituent  processes  are  dependent  in  a 
high  degree  upon  the  quantity  of  the  particular  chemical  sub- 
stances of  which  the  living  system  is  composed.  The  cycle  of 
the  individual  constituent  processes  of  this  system  is  determined 
in  the  most  delicate  manner  in  its  rapidity  and  extent,  by  the 
relative  quantities  of  the  individual  substances.  Associated  with 
an  alteration  in  the  rapidity  of  an  individual  constituent  process, 
there  would  also  be  a  relative  alteration  quantitatively  of  the 
substances.  And  with  the  increase  in  the  quantity  of  the  disin- 
tegration products,  and  also  the  increase  of  the  substances  for 
their  replacement,  there  would  result,  during  this  time,  an  altera- 
tion in  the  amount  of  interaction  of  the  molecules  of  the  other 
constituent  processes,  so  that  these  processes  secondarily  sutler 
an  alteration  in  rapidity  which  is  perceptil)le  after  long  continued 
involvement  of  the  functional  part  of  metabolism. 

In  fact,  in  the  previously  mentioned  case  of  the  functional 
stimulation  of  the  muscle,  the  proof  has  been  furnished  that  a 
long-continued  increase  of  the  functional  metabolism  is  fol- 
lowed, although  to  a  less  extent,  by  an  increase  in  the  entire 
cytoplastic  metabolism.  Argutinski  showed  this  on  liimsclf  in 
1890  in  Pfliigcr's  laboratory.  He  found,  namely,  that  after  tlie 
exertion  of  a  long  walk  in  a  hilly  district,  a  considerable  increase 
of  nitrogen  excretion  in  the  urine  took  place,  which  extended 


80  IRRITABILITY 

over  the  succeeding  two  or  three  days.     This  increase  of  the 
nitrogen  metaboHsm  in  its  totaHty  is  not  nearly  as  great  as  that 
of   the   breaking   down   of    nitrogen-free    substances,   but   it    is, 
nevertheless,  present  and  shows  us  that  functional  metabolism 
cannot  experience  a  lasting  excitation  without  being  followed  by 
secondary   results   in   the   entire   cytoplastic   metabolism.      This 
fact  is  even  more  strikingly  illustrated  in  the  alteration  of  the 
entire  volume  of  a  living  organism  as  produced  by  the  lengthened 
duration  of  functional  stimulation.    It  has  been  long  known,  that 
the  muscle  as  the   result  of   frequent   functional   excitation  by 
means  of  adequate  nerve  impulses,  that  is,  prolonged  activity,  is 
considerably  increased  in  size,  whereas  in  the  absence  of  such 
it  loses  more  and  more  in  volume.     A  hypertrophy  of  activity, 
produced  by  functional  stimuli,  and  the  atrophy  of  inactivity,  the 
result  of  the  discontinuance  of  the  functional  excitation,  is  uni- 
versal and  can  be  observed  in  the  various  tissues  of  our  body. 
We  see  it,  for  example,  in  the  glands ;  we  see  it  in  the  skin  and 
we  see  it  in  the  elements  of  the  nervous  system,     Berger,^  for 
instance,  established  the  fact  that  the  ganglion  cells  of  the  optic 
lobe   in   the   cerebrum   of   newborn   dogs   only   reach   their   full 
development  when  functionally  excitated  by  adequate  light  stim- 
uli (Figure  9,  B),  coming  from  the  eye,  whereas  they  remain  in 
the  embryonic  state  when  these  light  stimuli  are  eliminated.    (Fig- 
ure 9,  A.)    The  cytoplastic  increase  of  volume  of  the  neurons 
under  the  influence  of  functional  stimuli  is  a  fact  of  fundamental 
importance  for  the  entire  happenings  of  the  nervous  system  and 
forms  the  physiological  basis  for  reinforcement  of  reflexes,  which, 
in  its  turn,  is  essential  for  all  acts  of  memory  and  intelligence. 
For  the  increase  in  volume  of  the  ganglion  cell  body  is,  when 
functionally    activated,    accompanied    at    the    same    time    by    an 
increase  of   specific  capabilities  and  the  intensity  of   discharge. 
Its  excitation  impulses  can,  therefore,  be  conducted  through  a 
greater  number  of  neurons,  with  which  it  is  connected,  than  would 
be  the  case  if  development  of  the  volume  of  the  ganglion  cell 
increased  to  a  less  extent. 

1  Berger:  "Experimentell-anatomische  Studien  iiber  die  durch  den  Mangel  optischer 
Reize  veranlassten  Entwickelungschemmungen  im  Occipitallappen  des  Hundes  und 
der  Katze."     Arch.  f.  Psychiatrie,  Bd.  33,   1909. 


H 


FiU.  9. 

A— Undeveloped  ganglia  cells  in  the  optic  lobe  of  a  dog.  the  eyes  of  which  have  been 

sewn  up  immediately  after  birth.     B    Fully  developed  «an«lia  cells  in  the  same 

rnciinn  n(  1  nnrmil  i\nii  n{  the  '^Tmc  acc.     I  Aftcr  licracT.) 


82  IRRITABILITY 

The  increase  in  volume  under  the  influence  of  stimuH  further 
shows  the  relation  between  the  group  of  those  solely  catalytic 
effects  of  stimulation  consisting  in  mere  alterations  of  rapidity  of 
the  specific  vital  process,  and  that  of  the  metamorphotic  effects 
of  stimulation,  which  manifest  themselves  in  qualitative  altera- 
tions of  the  vital  process.  Simple  observation  shows  us  that  a 
qualitative  change  of  individual  constituent  processes  must  neces- 
sarily result  from  the  increase  of  volume  of  a  cell,  and  that  con- 
sidering the  close  correlation  of  all  the  individual  processes  a 
profound  alteration  of  the  entire  metabolism  must  be  produced. 
I  have  already  at  another  place  treated  these  conditions  more  in 
detail  and  will,  therefore,  only  briefly  refer  to  them  here.  If  we 
study  the  growth  of  a  ball-shaped  cell,  we  find  that  the  surface 
then  increases  as  a  square,  and  the  volume  as  the  cube.  It  there- 
fore follows  that,  by  progressive  volume  increase,  the  conditions 
for  the  interchange  of  substance  with  the  surrounding  medium 
must  become  more  and  more  unfavorable  for  those  cell  portions 
situated  in  the  interior,  whereas  those  at  the  exterior  are  at  much 
greater  advantage.  This  must  lead  to  a  constantly  increasing 
difference  of  the  rapidity  of  the  metabolic  processes  between  the 
peripheral  and  central  portions.  Accordingly,  the  intricate  inter- 
workings  of  the  individual  constituent  processes,  the  rapidity  of 
action  of  all  which  is  intimately  connected,  are,  therefore,  fol- 
lowed by  corresponding  alterations  in  the  entire  metabolism. 
Sooner  or  later  a  stage  is  reached  in  which  the  individual  constit- 
uent processes  become  so  limited  that  certain  metabolic  products, 
which  previously  were  broken  down  as  soon  as  formed,  can  be 
no  longer  eliminated  and  remain  in  the  cell  acting  as  foreign 
bodies.  In  this  way  the  relative  quantity  of  the  individual  cell 
substances  become  more  and  more  altered,  and  as  the  course  of 
chemical  processes  occurs  in  accordance  with  the  law  of  mass 
action,  the  whole  metabolism  is  directed  into  another  channel, 
so  that  finally  new  constituent  processes  take  place,  which  were 
formerly  not  possible.     These  in  their  turn  produce  deep-seated 

1  Max  Verworn:  "Die  cellularphysiologische  Grundlage  des  Gedachtnisses." 
Zeitschrift  f.  allgemeine   Physiologic,   Bd.   VI,   1907. 

2  Max  Verworn:  "Allgemeine  Physiologic."     V.  Aufl.  1909,  pages  649-671. 


THE  GENERAL  EFFECT  OF  STIMULATION       83 

alterations  of  the  relations  of  the  cell  to  its  surrounding  niediuin. 
etc.  Hence  this  mere  increase  of  volume  of  the  cell  in  growth 
forms  the  source  of  an  infinite  mass  of  alterations  in  the  activities 
of  cell  metabolism,  which  we  briefly  term  its  "dcvclopmcyit."  and 
wdiich  by  constant  progression,  leads  either  to  a  process  of  cell 
division,  and  with  this  to  a  correction  of  exi>ling  disorder,  or 
finally  to  irreparable  disturbances  ending  in  death.  In  this  way 
an  inseparable  relation  exists  between  increase  of  volume  and 
the  development  of  living  substance.  We  have  seen,  liowever, 
that  the  catalytic  reactions  of  stimulation,  which  at  first  only 
produce  an  alteration  of  rapidity  of  the  individual  constituent 
processes,  if  of  prolonged  duration  or  of  frecjuent  recurrence, 
secondarily  effect  a  change  of  volume  of  the  entire  living  organ- 
ism. One  can,  therefore,  hardly  reject  the  conclusion  that  seeing 
the  close  interworkings  of  the  individual  part  process  of  metab- 
olism, every  change  of  rapidity  of  a  single  member,  if  of  pro- 
longed duration  or  of  frequent  occurrence,  must  finally  lead  to 
qualitative  alterations  of  the  entire  metabolism.  In  consequence 
there  results  an  important  dependence  between  catalytic  stimula- 
tion and  metamorphic  reaction.  Indeed,  it  is  not  unlikely  that 
the  metamorphic  reactions,  which  are  especially  seen  in  the  con- 
tinued effect  of  weak  stimuli,  result  from  alterations  of  rapidity, 
w^hich  the  individual  members  of  the  vital  processes  have 
primarily  undergone  from  this  influence. 

It  is  perhaps  expedient  to  cite  a  concrete  instance  in  illustration. 
A  simple  example  is  furnished  by  as])hyxiation.  If  oxygen  is 
withdrawn  from  any  living  organism,  the  result  is  a  depression 
of  its  oxydation  processes.  Here  there  is  primarily  only  a  change 
in  rapidity,  especially  a  retardation  of  oxydation  processes.  The 
metabolism,  however,  proceeds,  the  disintegration  of  living  sub- 
stance continues,  although  at  a  slower  rate,  but  produces  an 
accumulation  of  other  products.  Whereas  formerly  during  the 
existence  of  a  sufficient  supply  of  oxygen  an  oxydative  disintegra- 
tion of  nitrogen-free  groups  into  carl)on  dioxide  and  water  took 
place,  both  of  which  could  easily  be  eliminated  from  the  cell,  the 
anaerobic  disintegration  furnishes  only  complex  ])r(Hlucts.  having 
a  higher  carbon  content,  such  as  lactic  acid,  fatty  acids,  aceton. 


84  IRRITABILITY 

etc.  These,  being  more  difficult  to  excrete  from  the  cell,  accumu- 
late. These  asphyxiation  products  have  in  their  turn  a  depressing 
effect  and  so  on.  In  this  way  the  whole  metabolism  is  forced  into 
a  wrong  course.  The  accumulation  of  fat  in  those  tissue-cells 
with  an  insufficient  blood  supply,  as  we  have  seen  in  the  case  of 
the  fat  metamorphosis,  is  doubtless  brought  about  in  the  same 
manner  by  relative  oxygen  insufficiency.  The  fatty  acids  accumu- 
late as  products  of  an  incomplete  combustion  and  combine  with 
glycerine  to  form  neutral  fats.  In  like  manner  it  may  be  that  the 
accumulation  of  amyloid  substance  in  amyloid  metamorphosis,  of 
lime  salts  in  arteriosclerosis,  etc.,  is  produced  by  a  primary 
depression  of  the  individual  constituent  processes  of  the  particu- 
lar cells. 

The  relation  here  described,  of  the  catalytic  stimuli  to  the  pro- 
duction of  the  metamorphic  processes,  leads  us  to  the  dis- 
tinctions between  primary  and  secondary  effects  of  stimulation. 
Should  the  general  fact  be  established,  which  has  up  to  now  only 
been  pointed  out  in  individual  cases,  that  all  the  metamorphic 
processes  are  merely  secondary  results  of  primary  alterations  in 
rapidity  of  individual  metabolic  constituent  processes,  then  the 
primary  reactions  of  every  stimulus  would  consist  purely  in  the 
excitation  or  depression  of  the  directly  concerned  constituent. 
Whether  or  not,  as  may  be  assumed,  this  primary  effect  of  stimu- 
lation applies  to  all  stimuli,  is  a  question  which  only  the  future 
can  answer. 

The  metamorphic  processes  are  not,  however,  the  only  sec- 
ondary effects  of  stimulation.  The  influence  of  long-continued 
excitation  of  the  functional  constituent  processes  upon  the  entire 
cytoplastic  metabolism  can  be  looked  upon  as  a  secondary  re- 
sponse. Therefore,  they  may  be  considered  as  a  secondary  effect 
of  stimulation  which,  in  contrast  to  this  primary  excitation,  may 
be  called  the  secondary  excitation. 

Further :  While  the  secondary  excitation  and  metamorphic 
processes  are  generally  produced  by  the  continued  existing  effects 
of  weak  stimulation,  we  also  observe  as  the  result  of  a  stimulus 
of  short  duration  or  frequently  repeated  at  brief  intervals,  but 
otherwise  not  exceeding  the  physiological  limits  of  intensity,  a 


THE  GENERAL  EFFECT  OF  STIMULATION       85 

secondary  effect,  which  ])lays  a  very  imi)ortant  jKirt  in  ilie  activity 
of  the  organism.  I  refer  to  fatigue.  Here  a  secondary  depres- 
sion is  developed  in  connection  with  tlie  primary  excitation,  for 
fatigue  of  a  hving  organism  must  be  cliaracterized  as  a  depression 
of  activity.  This  case  shows  that  we  liavc  to  distinguish  between 
a  primary  depression,  as  for  exanii)lc.  i)r()(hiced  by  tcmj)craturc 
reduction,  withdrawal  of  food,  deficiency  of  oxygen,  etc.,  which 
occurs  as  a  direct  effect  of  stimulation,  and  secoudary  depression, 
W'hich  as  in  fatigue  is  an  indirect  result  of  primary  excitation. 

After  the  cessation  of  a  briefly  catalytic  stimulus,  n(ji  exceed- 
ing the  physiological  limit  of  intensity,  another  secondary  result 
is  observed,  which  is  of  the  greatest  importance  for  the  con- 
tinued existence  of  the  living  substance.  The  catalytic  stimulus 
brings  about  a  disturbance  of  the  ecjuilibrium  of  metabolism, 
which  after  cessation  of  the  stimulus  is  reestablished  l)y  the  living 
substance.  In  other  words:  recovery  takes  j)lace.  This  funda- 
mental principle  has  been  known  for  a  long  time  as  the  result 
of  observation.  If  a  skeletal  muscle  of  our  body  has  been  acti- 
vated for  a  prolonged  period  by  nerve  impulses,  until  it  has 
become  completely  fatigued  and  incapable  of  work,  a  recovery 
takes  place  on  the  cessation  of  these  impulses  and  the  muscle  is 
again  capable  of  action.  Likewise,  as  the  result  of  strong  mental 
activity  during  the  day,  we  are  mentally  fatigued  in  the  evening : 
recovery,  however,  occurs  during  the  night,  which  results  from 
the  removal  of  the  source  of  activity.  The  next  morning  fmds 
us  refreshed.  This  restitution  occurs  in  every  cell,  and  the  return 
of  its  former  capability  of  action,  which  had  disappeared  under 
the  influence  of  stimulation,  shows  that  compensation  has  taken 
place  of  the  metabolism  of  rest,  disturbed  by  the  effects  of  the 
stimulus.  Herincf  has  aptly  termed  this  restitution  as  "the  inter- 
nal self-regulation  of  metabolism."  All  recovery  after  disease  is 
based  on  this  self-regulation.  The  physician  simjily  jirovides.  by 
means  of  therapy,  for  the  possibility  of  its  taking  i)lacc.  Healing 
itself  is  brought  about  by  the  organism.  'W'atura  sanat.  medieus 
curat." 

1  Ewald  Herxng:  "Zur  Theorie  der  Vorgiiiigc  in  dcr  IcbcntliRcn  Sub»tan/."  In 
Lotos,   Bd.    19,  Prag.    1888. 


86  IRRITABILITY 

Finally,  a  third  kind  of  secondary  effect  of  stimulation  claims 
our  interest.  This  is  the  secondary  extension  of  the  result  of 
stimulation  from  the  part  of  a  living  organism  directly  and  pri- 
marily affected  by  the  stimulus,  to  the  surrounding  structures. 
All  living  substance  has  the  capability  of  conducting  an  excitation, 
which  is  produced  locally  through  a  catalytic  stimulus,  to  a  neigh- 
boring part,  not  directly  affected  by  the  stimulus.  It  finds  its 
highest  development  in  the  nerve,  but  in  no  living  structure  is  it 
completely  absent.  This  capability  has  been  frequently  termed 
"conductivity  of  stimulation."  It  is  more  precise,  however,  to 
speak  of  conductivity  of  excitation,  for  it  is  not  the  primary 
influencing  external  stimulus  which  is  conducted  in  the  living 
substance,  but  the  excitation  which  it  has  produced.  I  have  inten- 
tionally considered  only  the  excitating  effects  of  stimulation,  and 
not  those  of  the  depressing  reactions,  as  only  excitations,  not 
depressions,  are  conducted  by  the  living  substance.  These  ques- 
tions, however,  demand  a  closer  analysis.  Here  we  were  con- 
cerned only  with  a  survey  of  the  general  effects  of  stimulation. 
If  I,  therefore,  once  more  summarize  the  results  which  have  been 
gained,  this  is  most  clearly  demonstrated  by  the  following  scheme : 

Primary  Effects  of  Stimulation 

Excitation      Depression 
Functional     Cytoplastic     Functional 

Secondary  Effects  of  Stimulation 

Secondary  excitation        Secondary  depression 
Conduction    of    excitation,    Metamorphic    processes,    Self-regulation    of 

metabolism 

This,  however,  is  simply  a  scheme,  like  all  other  schemes,  having 
for  its  purpose  a  superficial  survey  of  the  subject. 

It  brings  to  some  extent  order  into  the  overwhelming  mass  of 
manifold  effects  of  stimulation  but  tells  us  nothing  of  the  mech- 
anism and  genesis.  Our  further  task  must,  therefore,  be  a  more 
thorough  analysis  of  this  field. 


chapti^:r  V 

THE  ANALYSIS  OF  THE  PROCESS  OF  ICXCFIATIOX 

Contents:  Indicators  for  the  invcsti^^ation  of  the  process  of  excitation. 
Latent  period.  The  question  of  the  existence  of  assimilatory  excita- 
tions. Dissimilatory  excitations.  Excitations  of  the  partial  compo- 
nents of  functional  metabolism.  Production  of  energy  in  the  chemi- 
cal splitting  up  processes.  Oxydative  and  anoxydative  disinteRration. 
Theory  of  oxydative  disintegration.  Dependence  of  irritability  on 
oxygen.  Experiments  on  unicellular  organisms,  nerve  centers  and 
nerve  fibers.  Restitution  after  disintegration  by  metabolic  self- 
regulation.  Organic  reserve  supplies  of  the  cell.  The  question  of  a 
reserve  supply  of  oxygen  of  the  cell.  Metabolic  self-regulation  as  a 
form  of  the  law  of  mass  effect,  and  metabolic  equilibrium  as  a  con- 
dition of  chemical  equilibrium.     Functional  hypertrophy. 

If  it  is  true  that  all  primary  eflfects  of  .'Stimulation  consist  cither 
in  an  excitation  or  depression  of  the  metabolism,  and  that  all  other 
effects  of  stimulation  secondarily  follow  this  primary  alteration 
of  the  metabolism  of  rest,  then  every  thorough  analysis  of  the 
mechanics  of  reaction  must  have  its  beginning  in  the  investiga- 
tion of  these  primary  processes.  I  desire  to  adopt  this  method 
here  and  will  analyze  somewhat  further  the  primary  process  of 
excitation  and  its  immediate  and  remote  sequences.  This  will  be 
followed  later  by  the  analysis  of  the  process  of  primary  depres- 
sion and  its  results. 

The  investigation  of  the  more  obscure  processes  in  the  living 
substance  places  us  in  a  difiicult  position,  for  their  details  cannot 
be  observed  bv  the  unaided  senses.  That  which  we  can  perceive 
is  merely  the  grosser  vital  action,  consisting  of  a  c()mi>lex  combi- 
nation of  the  individual  processes,  the  total  result  of  a  nuiltitude 
of  different  components.  For  this  reason  the  conception  of  exci- 
tation can  only  be  established  by  observations  based  upon  the 
combined  vital  actions,  which  are  produced  by  the  effect  of  stinui- 


88  IRRITABILITY 

lation  upon  the  complex  system.  In  the  beginning,  the  process 
of  excitation  was  studied  exclusively  on  the  muscle  and  nervous 
system.  A  physical  factor  served  as  indicator,  such  as  muscle 
contraction  or  production  of  electricity.  These  showed,  besides 
the  direct  and  primary  effect  of  stimulation,  the  secondary  pro- 
cess of  conductivity.  Even  graphic  registration  is  merely  an 
expression  of  the  phenomena  composed  of  a  great  mass  of  indi- 
vidual elements.  The  visible  course  of  the  phenomena,  as  shown, 
for  instance,  by  the  latent  period  by  the  ascent  and  descent  of  the 
curve  of  contraction,  represents  as  it  were  a  reflected  picture  of 
the  actual  excitation  processes  similar  to  an  object  seen  in  a  dis- 
torting mirror ;  the  first  and  the  last  parts  of  the  process  are  not 
even  perceptible.  Later,  when  organ  physiology  was  extended 
into  a  cell  physiology  the  processes  of  excitation  were  studied  in 
numerous  simple  organisms,  such  as  the  plant  cell,  the  rhizopoda, 
the  infusoria,  etc.  Later,  in  this  way,  by  the  use  of  compara- 
tive methods  many  essential  facts  were  discovered.  However, 
even  the  single  cell,  in  spite  of  its  minuteness,  is,  compared  with 
the  size  of  a  molecule,  a  gigantic  system,  and  it  would  be  a  grave 
error  if  we  should  consider  this  system  even  in  its  simplest  aspect 
as  homogeneous.  In  order,  therefore,  to  analyze  the  vital  activi- 
ties in  the  cell,  cell  physiology  must  endeavor  to  penetrate  into 
molecular  conditions.  For  this  purpose  the  indicators  employed 
must  be  essentially  of  a  chemical  nature,  capable  of  magnifying 
the  processes  of  molecular  dimension  to  such  a  degree  that  we 
are  enabled  to  base  conclusions  upon  these  not  otherwise  directly 
perceptible  phenomena.  To  obtain  a  sufficient  magnification  we 
must  necessarily  place  somewhat  larger  quantities  of  living  sub- 
stance under  observation  and  apply  a  stimulus  of  such  frequency 
or  length  of  duration  that  the  chemical  alterations  as  a  result  of 
excitation  are  so  increased  as  to  be  plainly  perceptible  with  the 
aid  of  our  chemical  indicators.  Unfortunately,  we  do  not  pos- 
sess specific  chemical  indicators  for  every  individual  molecular 
constituent  process  of  the  cell  and  so  cannot  dispose  with  the  help 
of  indicators  of  the  combined  happenings  in  a  greater  quantity  of 
living  substance.  It  remains  for  us  to  obtain  data  concerning  the 
cycle  of  excitation  processes  in  the  living  substances  by  the  aid 


THE  PROCESS  OE  EXCITATION'  89 

of  the  combined  employment  of  the  most  varied  kinds  of  physical 
as  well  as  chemical  indicators.  If  we  use  the  most  varied  types  of 
living  substance  of  widely  differing  proi)erties,  showing  us  the 
greatest  variety  of  vital  manifestations,  we  may  hope  by  the  use 
of  comparative  physiological  methods,  even  though  with  diffi- 
culty, to  separate  more  and  more  the  essential  details  of  the  gen- 
eral processes  of  excitation.  At  present  we  are  still  at  the  very 
beginning  of  this  task  and  vast  fields  of  unexplored  regions  arc 
yet  before  us.  But  it  is  the  unknown  which  has  a  particular  fasci- 
nation, especially  if  we  succeed  from  time  to  time  in  making  new 
advances. 

If  we  suppose  a  living  system  in  a  state  of  metabolism  of  rest 
influenced  by  an  instantaneously  excitating  stimulus,  the  entire 
course  of  excitation  extends  from  the  first  alteration  i)roduced 
by  the  stimulation  until  the  complete  restitution  of  the  metabolic 
equilibrium,  and  we  will,  therefore,  differentiate  individually  the 
successive  stages  of  this  whole  process. 

The  very  beginning  of  the  chain  of  alterations  produced  by  the 
excitating  stimulus  cannot  be  studied  by  any  indicator.  The 
changes  must  first  reach  a  certain  dimension  by  conduction  from 
the  point  of  stimulation  before  they  influence  even  the  most  deli- 
cate indicators.  The  application  of  the  stimulus  is,  therefore, 
followed  at  first  by  a  measurable  "latent  period,"  in  which  the 
living  substance  remains  apparently  at  rest.  This  latent  period 
has  been  particularly  studied  in  muscle.  After  its  discovery  by 
Helmholtz'^  it  was  made  the  object  of  innumerable  investigations 
and  met  with  an  interest  which  can  only  be  explained  by  the  exact- 
ness of  the  methods  employed.  Among  others  Tigcrstcdt-  has 
made  the  most  thorough  study  of  the  influence  of  various  factors 
on  the  duration  of  the  latent  period.  1  hese  experiments  have 
established  the  fact  that  the  duration  of  the  latent  period  varies 
according  to  the  intensity  of  the  stimulus,  temperature,  loading 

1  Hclmholtz:  "Messungen  iiber  den  zcitlichen  Vcrlauf  der  Zuckungcn  animaliwhcr 
Muskeln  und  die  Fortpflanzungsgeschwindigkeit  der  Reizung  in  den  Nervcn."  .\rchiv 
fiir   Physiologic  Jahrgang   1850. 

2  Robert  Tigcrstcdt:  "Untersuchungen  iiber  die  I^tenzdaucr  der  Muskeliuckung 
in  ihrer  Abhangigkeit  von  verschiedenen  Variablen."  Arch.  f.  Physiologie  Jahrgang 
1885    Suppl. 


90  IRRITABILITY 

or  fatigue.  This  is  apparent  when  it  is  understood  that  the 
amount  of  the  alterations  produced  by  the  stimulus  must  ascend 
from  the  value  zero  to  a  certain  height  before  the  changes  are 
perceptible,  and  that  under  various  conditions  this  amount  is,  on 
the  one  hand,  attained  in  different  lengths  of  time  and,  on  the 
other,  must  reach  a  varying  amount  before  it  is  perceptible  by 
means  of  the  indicator. 

The  facts  concerning  the  whole  latent  period  and  its  depend- 
ence on  various  factors  would  be  incomprehensible  if  it  were 
assumed  that  no  alterations  whatever  take  place  during  the  latent 
period  although  the  stimulus  is  already  operative.  In  reality,  the 
alterations  following  a  stimulus  occur  with  imperceptible  rapidity 
in  the  form  of  a  molecular  interchange,  and  the  latent  period  is 
simply  an  expression  of  the  fact  that  the  primary  alterations, 
being  limited  in  nature,  are  not  registered  by  our  indicators. 

The  question  first  arises,  In  what  do  these  first  imperceptible 
alterations  consist?  Nernst^  has  evolved  the  theory  for  electric 
stimulus,  that  the  primary  effect  produced  by  the  electric  current 
is  an  alteration  in  the  ion  concentration  on  the  surface  of  the 
living  substance.  In  fact,  we  know  that  the  surfaces  of  all  proto- 
plasm possess  the  property  of  semi-permeable  membranes  and  that 
changes  in  the  concentration  of  ions  invariably  occur  when  an 
electric  current  flows  through  two  electrolytes  separated  by  a 
semi-permeable  membrane,  in  which  the  anions  and  cations  have 
a  different  rapidity  of  movement.  It  is  apparent,  therefore,  that 
such  an  alteration  in  the  ion  concentration  must  be  followed  by 
further  chemical  processes  in  the  living  substance.  According 
to  the  theory  of  Nernst  the  first  impetus  for  all  further  altera- 
tions, which  the  electrical  stimulus  brings  about  in  the  metabolism 
of  rest,  is  the  alteration  in  the  concentration  of  the  ions  on  both 
sides  of  the  semi-permeable  membrane,  which  represents  the  sur- 
face of  the  protoplasm.  In  view  of  the  present  findings  of  physi- 
cal chemistry,  objections  can  hardly  be  made  to  this  theory  of 
Nernsfs.  It  is  a  question,  however,  in  how  far  this  theory,  espe- 
cially established  for  the  electric  stimuli,  can  be  applied  to  other 

\  Nernst:  "Zur  Theorie  der  electrischen  Reizung."  Nachrichten  der  Konigl. 
Gesellsch.  d.  Wissensch.  zu  Gottingen.     Math,   physik.   Klasse   1899. 


THE  PROCESS  OF  EXCITATION  91 

forms  of  stimuli  and  their  action.  It  cannot  he  denied  that  the 
degree  of  dissociation  of  an  electrolyte  can  be  altered  by  very 
different  factors,  such  as  heat,  light,  chemical  processes,  etc., 
and  in  that  the  surfaces  of  the  protoplasm,  acting  as  semi- 
permeable membranes,  bring  about  a  selective  action  on  the  pas- 
sage of  the  ions,  there  arises  the  opi)ortunity  f(^r  the  develoi)ment 
of  difference  of  electrical  potential  on  both  sides,  and  for  further 
chemical  alterations  in  the  prot()i)lasni.  These  observali(jns,  how- 
ever, require  further  experimental  investigations  in  many  fields, 
before  we  are  justified  in  extending  the  Ncrnst  theory  of  the 
manner  of  action  of  the  electric  stimuli  to  a  general  ex])lanation 
of  the  primary  alterations  produced  by  all  stimuli  in  the  living 
substance.  For  the  present  we  must  confine  our  observations  to 
those  alterations  which  are  known  to  be  resi)onses  to  an  exci- 
tating  stimulus;  these  are  the  chemical  alterations  in  the  metab- 
olism of  rest  in  the  living  substance. 

If  it  is  asked,  which  members  of  the  entire  metabolic  chain 
are  increased  primarily  by  the  stimulating  excitation  of  a  vital 
system,  we  should  not  be  able  to  answer  this  question  gen- 
erally for  all  living  systems.  To  begin  with,  it  appears  highly 
probable  that  the  various  forms  of  vital  substances  in  this  res|>ect 
act  quite  differently.  It  is  to  be  regretted  that,  up  to  the  present, 
this  question  has  not  been  treated  from  a  comparative  stand- 
point. This  inquiry  should  be  extended  to  the  greatest  ix)ssible 
number  of  organisms.  Still  there  is  enough  material  at  hand, 
obtained  from  the  muscles,  glands,  ganglion  cells,  nerve  fibers 
and  plants,  to  show  that  the  complexity  is  by  no  means  so  great 
as  one  might  at  first  assume. 

In  considering  the  two  stages  of  metabolism,  assimilation  and 
dissimilation,  in  their  entirety,  it  ai)pears  as  a  very  remarkal)lc 
fact,  that  nearly  all  stimuli  produce  primarily  a  dissimilath-c 
excitation.  We  are  only  accjuaintcd  with  a  primary  asstmt- 
lative  excitation,  that  is,  an  augmentation  of  the  building  up 
processes,  in  short,  the  formation  of  living  substance,  occurring 
as  a  primary  result  of  stimulation,  following  increased  intro- 
duction of  foodstuffs  extending  over  a  prolonged  length  of  time. 
With  this  exception  it  cannot  be  proved  that  any  other  stimuli, 


92  IRRITABILITY 

either  especially  those  operative  in  the  activity  of  the  animal 
organism  or  any  of  the  physiological  nerve  impulses  which  regu- 
late the  actions  of  the  different  organs  and  tissues,  bring  about 
primarily  an  assimilative  excitation,  which  leads  to  an  increase 
of  new  formation  of  living  substance.  The  much-discussed 
teaching  of  the  existence  of  the  trophic  nerves  has  not  given  us 
a  single  case  in  which  there  was  positive  proof  that  a  nerve 
impulse  brought  about  a  primarily  assimilative  excitation.  I  have 
endeavored  for  nearly  fifteen  years  to  discover  such  a  case. 
My  efforts  have  been,  however,  without  avail.  In  the  most  recent 
critical  review  by  Jensen^  on  the  subject  of  the  trophic  nerves,  the 
same  conclusion  is  reached  although  certain  facts,  as,  for  instance, 
the  excitation  of  assimilative  processes  in  the  green  plant  cell, 
produced  by  light,  seems  at  the  first  glance  to  clearly  demonstrate 
a  primary  excitation  of  the  building  up  processes  resulting  from 
a  stimulation.  Nevertheless  closer  observation  invariably  shows 
that  these  conditions  are  much  more  complicated  and  that  pri- 
marily assimilative  excitating  reaction  of  the  stimulus  cannot  be 
conclusively  shown.  There  remains,  therefore,  as  a  primary 
assimilative  excitating  stimulus  only  the  increased  introduction 
of  nutrition  in  a  living  organism.  This  excitating  effect  on  the 
assimilative  portion  of  metabolism  is,  as  we  shall  see  later,  a 
simple  manifestation  of  the  law  of  mass  action. 

As  a  result  manifold  effects  of  excitating  stimulation,  which 
seemed  possible  at  a  first  glance,  are  already  considerably  re- 
stricted. The  great  mass  of  excitating  stimuli  produce  an  accel- 
eration of  the  dissimilative  processes  of  the  metabolic  chain.  But 
here  our  former  observations  have  already  shown  that  certain 
constituent  processes  are  especially  responsive  and  very  readily 
increase  as  a  result  of  the  most  varied  adequate  and  inadequate 
stimuli.  These  are  the  "functionaV'  members  of  metabolism. 
These  members  are  particularly  labile,  so  that  they  are  always 
affected  by  every  influence  to  which  the  system  is  subjected  in 
the  form  of  a  stimulus.  The  functional  portion  of  metabolism 
of  the  muscle,  which  is  particularly  labile  and  is  always  primarily 

1  Paul  Jensen:  "Das   Problem   der   trophischen   Nerven."      Medicinisch-naturwissen- 
schaftliches  Archiv.  Bd.  II,   1910. 


THE  PROCESS  OF  EXCITATION  93 

affected  by  stimulalion,  consists  as  demonstrated  in  increase 
of  formation  of  carbon  dioxide  and  water,  and  in  tlie  disintegra- 
tion of  the  nitrogen-free  groups.  The  innumerable  observations 
on  metabohsm  during  the  stage  of  tlie  activity  of  the  muscle,  as 
those  of  Hermann,  v.  Frcy,  Fletcher,  Joluiunson,  I'huubcnj, 
and  many  others  on  the  individual  nuiscle,  and  those  by  I'oit, 
Pick  and  Wisliceniis,  PfliUjer,  Riibner,  Ziiutz.  Lehmann  and 
Hagemann,  Bernstein  and  Lowy  and  others  on  the  nuiscle  of  the 
entire  organisms,  have  sufficiently  proved  this  fact.  However,  we 
should  not  apply  in  detail  the  conditions  existing  in  the  muscle 
to  all  living  substance.  Comparative  methods  show  us.  rather, 
that  the  functional  portion  of  metabolism  is  very  (hfferently 
involved  in  various  forms  of  living  substance.  The  formation  of 
carbon  dioxide  and  water  is  constant  in  nearly  all  forms  of  living 
substance.  We  must,  however,  exclude  certain  micro-organisms, 
which  have  adapted  themselves  to  unusual  vital  conditions. 
Further,  there  appear  in  some  forms  manifold  special  constit- 
uent processes  consisting  in  a  disintegration  of  living  substance 
which  are  in  part  converted  into  very  complex  combinations.  In 
the  gland  cells  this  type  is  represented  in  an  especially  high  degree. 
Here  the  functional  disintegration  leads  to  excretion  of  proteins, 
glycoproteins,  nucleoproteins,  cholic  acid,  enzymes  of  various 
kinds,  all  of  which  are  complex  and  at  the  same  time  nitrogenous 
organic  combinations.  This  fact  must  not  be  lost  sight  of.  The 
origin  of  these  special  members,  however,  for  the  present  is  com- 
pletely unknown,  wdiile  on  the  other  hand,  it  is  self-evident  that 
the  general  and  constant  constituents  of  the  process  of  excitation 
must  claim  a  first  place  in  our  interest.  It  is  just  at  this  point. 
therefore,  that  wt  must  endeavor  to  penetrate  somewhat  more 
deeply  into  the  mechanism  of  the  excitation  process  and  analyze 
in  greater  detail  the  acceleration  of  the  functional  constituent 
parts  of  metabolism  produced  by  the  stimulus  bringing  about  the 
formation  of  carbon  dioxide  and  water. 

The  question  arises :  By  what  means  is  the  /^articular  labile  state 
of  just  this  constituent  part  of  functional  metabolisf.i  conditioned f 
The  lability  of  the  functional  portion  of  metabolism,  excitated 
by  the  stimulus,  resembles  the  processes  in  the  disintegration  of 


94  IRRITABILITY 

explosive  combinations.  Iodide  of  nitrogen,  for  instance,  in  a 
manner  similar  to  the  living  substance  in  the  state  of  the  metab- 
olism of  rest,  constantly  disintegrates  even  without  the  influence 
of  an  impact.  The  disintegration  is  suddenly  enormously  in- 
creased by  the  result  of  a  jar.  An  explosion  follows.  In  a  like 
manner  the  functional  metabolism  of  rest  is  explosively  exci- 
tated  by  the  stimulus,  the  transformation  of  the  energy  involved 
likewise  bears  a  similar  relation. 

In  both  instances  the  transformation  of  energy,  constant  in  the 
resting  state,  is  by  the  impact  of  the  stimulus  suddenly  increased. 
The  dynamic  method  of  investigation  of  the  excitation  process 
with  its  physical  indicators,  forms,  therefore,  in  many  respects 
an  excellent  addition  to  the  chemical  analysis.  A  development, 
that  is,  exothermic  formation,  of  energy  can  only  occur  in  a 
chemical  process  when  the  chemical  affinities  which  are  to  be 
combined  are  stronger  than  those  which  have  been  separated. 
When  this  process  is  brought  about  by  a  simple  impact,  the  energy 
value  of  which  bears  no  relation  to  that  of  the  quantity  of  energy 
in  the  process  itself  and  which  occurs  with  explosive  rapidity, 
then  it  can  be  simply  a  question  of  a  liberation  process,  that  is, 
a  process  by  which  the  impact  brought  about  a  conversion  of 
latent  chemical  energy  into  that  of  kinetic  energy.  The  compari- 
son of  the  functional  excitation  process  with  that  of  an  explosion 
does  not,  therefore,  consist  in  a  merely  superficial  analogy,  but  is 
founded  on  the  same  dynamic  principles. 

When  we  study  the  chemical  process  which  occurs  in  the  explo- 
sive transformation  of  potential  into  kinetic  energy  we  find  two 
types  of  chemical  processes.  The  first  type  includes  the  synthetic 
processes.  For  this,  the  synthesis  of  water  from  explosive  gas 
may  serve  as  a  simple  example.  Here  the  weaker  affinities  in 
comparatively  simple  molecules  (H  -|-  H  and  O  +  O)  are  sepa- 
rated and  stronger  affinities  are  combined  in  the  formation  of 
more  complicated  molecules  (H-fO  +  H).  The  second  type 
represents  the  process  of  cleavage.  As  example  for  the  latter,  the 
explosive  disintegration  of  nitroglycerine  may  be  quoted.  Here 
the  atoms,  held  together  in  a  complex  molecule  by  weaker  affini- 
ties,  are   changed  by   transposition   of   nitroglycerine.      For   in- 


THE  PROCESS  OF  EXCITATION 


95 


stance,  the  hydrogen  atoms  loosely  coml)inc(i  with  carbon  enter 
into  strong  combinations  with  oxygen  and  the  oxygen  loosely 
combined  with  the  nitrogen  enters  into  strong  combination  with 
carbon,  so  that  water  and  carbon  dioxide  are  fomicd  and  nitrogen 
and  oxygen  set  free. 


C-H 


c 

I 


■H 
■O-H 


O-Nto 


o  -h  C 


'O 


=  5HO+6CO+5N  +0 

2  Z  * 


o 
o 


In  the  functional  disintegration  of  living  substance,  the  last 
type  is  realized.  Living  substance  contains  loose  complex  com- 
binations, and  we  know  that  functional  disintegration  is  accom- 
panied by  the  consumption  of  these  organic  combinations.  In 
the  functional  disintegration  of  muscle  substance  the  nitrogen- 
free  groups  are  concerned,  and  we  must,  consequently,  tirst  con- 
sider the  carbohydrates.  However,  without  further  study  we 
should  not  generalize  from  that  which  is  true  in  the  case  of 
muscle.  There  are  other  forms  of  living  substances  which  con- 
tain different  combinations,  which  disintegrate  as  a  result  of  the 
contact  of  a  stimulus  and  yield  carbon  dioxide.  A  clue  as  to 
which  combinations  in  individual  cases  undergo  disintegration 
as  a  result  of  excitating  stimulation,  is  furnished  by  the  metab- 
olism of  rest  in  the  particular  substance.  Plants  and  micro- 
organisms have  been  investigated  more  thoroughly  in  this  con- 
nection than  animals.     Plant  physiology  has  demonstrated  that 


96  IRRITABILITY 

the  material  employed  for  the  COo  formation  and  with  it  the 
production  of  energy  is  carbohydrate,  but  that,  on  the  other  hand, 
various  plant  organisms  and  protistse  also  use  a  quantity  of  other 
substances,  such  as  fats  and  protein,  indeed  even  such  compara- 
tively simple  organic  combinations  as  alcohol,  formic  acid  and 
methan.  It  may  be  accepted  that  in  all  these  various  instances 
of  excitation  of  the  functional  metabolism  as  a  result  of  stimu- 
lation, the  specific  respiratory  material  of  the  substance  con- 
cerned is  used  in  greater  amount  in  the  decomposition  and  like- 
wise invariably  yields  carbon  dioxide. 

The  point  of  most  essential  interest  for  the  analysis  of  the 
excitation  processes  is,  above  all,  the  mechanism  of  the  organic 
combustion  and  the  associated  energy  production.  Here  we  may 
base  our  observations  on  the  disintegration  of  carbohydrates, 
which  is  most  extensive  in  the  animal  as  well  as  in  the  vegetable 
kingdom.  We  may  now  ask  how  dextrose,  for  instance,  dis- 
integrates in  the  living  system  into  carbon  dioxide,  for  it  is  this, 
or  a  sugar  of  similar  chemical  nature,  which  is  generally  con- 
cerned. Plant  physiology,  which  here,  as  in  many  other  respects, 
is  in  advance  of  animal  physiology,  has  indicated  two  ways  by 
which  this  can  be  accomplished  in  the  living  substance.  One  is 
oxydative,  the  other,  awoxydative  disintegration. 

In  the  oxydative  disintegration  of  dextrose,  taking  place  in 
aerobic  organisms,  if  sufficient  quantities  of  oxygen  are  present, 
there  occurs  a  splitting  up  of  the  carbohydrate  molecule,  as  a 
result  of  the  introduction  of  oxygen,  into  simpler  substances  and 
finally  into  carbon  dioxide  and  water,  just  as  the  dextrose  mole- 
cule, when  subjected  to  oxdyative  processes,  is  split  up  into  sim- 
pler molecules.  In  the  living  substance  the  oxydases  play  the 
important  role  of  oxygen  carriers.  It  cannot  be  denied,  however, 
that  up  to  now  no  carbohydrate  splitting  oxydases  have  been 
obtained  from  living  substance.  This,  of  course,  does  not  prove 
its  nonexistence.  But  this  deserves  consideration  in  connection 
with  an  assumption  very  widely  spread  among  plant  physiologists 
in  regard  to  the  aerobic  disintegration  of  the  carbohydrate  mole- 
cule, which  I  shall  touch  upon  presently.  If  we  suppose  that 
oxydases  exist,  which  bring  about  primarily  the  oxydative  disin- 


THE  PROCESS  OF  EXCITATION'  97 

tegration  of  the  dextrose  molecule,  its  first  point  of  attack  must 
obviously  be  sought  in  the  aldehyd  ^ninij).      Mere  would  l>c  sit- 
uated the  activator,  as  it  were,  for  the  whole  carbon  cliain.  from 
which,  as  by  a  sjiark,  the  entire  series  of  links  would  be  ignited. 
In   an  anoxydativc  disintcynitioti   of   dextrose  as  observed   in 
anaerobic  as  well  as  in  aerobic  organisms,  provided  the  latter  have 
an    insufficient    supi)ly    of    oxygen,    the    dextrose    molecule,    by 
enzymic  action  as  a  result  of  the  splitting  olY  of  carbon  dioxide, 
is  converted  into  substances  having  a  comi)aratively  large  carlxjn 
content.      The   best-known   exam])le   of   this   anoxydativc   disin- 
tegration is  the  formation  of  alcohol  by  fermentation  in  which 
the  dextrose  molecule  is  si)lit  u])  by  the  yeast  into  alcohol  and 
carbon  dioxide.      (C,;  H^oOo  =  2CoH^()H -f- 2COo.)      Instead   of 
the  production  of  alcohol  and  CO^  we  may  have  other  enzymic 
actions  with  the  formation  of  other  carl)on-containing  disintegra- 
tion products,  such  as  lactic  acid,  fatty  acids,  hydrogen,  etc.    Of 
course  in  such  an  anoxydativc  disintegration,  which  does  not  lead 
to  the  formation  of  such  simple  combinations  as  carlxjii  dioxide 
and  water,  the  quantity  of  energy  set  free  is  much  less  in  amount 
than  in  complete  oxy dative  decomposition,  the  energy  production 
of  the  alcohol  fermentation  being  only  1 1  per  cent  of  the  latter. 
In  order  to  produce  the  same  amount  of  energy  as  in  the  former, 
a  much  greater  number  of  molecules  is  required.     We  find,  there- 
fore, that  the  anoxydativc  type  of  disintegration  develops  either 
only  where  the  respiratory  substances  are  ])resent   in   sutVicient 
amounts,  as  for  instance,  in  the  case  of  yeast  cells,  existing  in 
nutritive    solutions    rich    in    sugar;    or    where    the    chemical    and 
energy  transformations  occur  only  to  a   limited  extent,  as,   for 
example,  in  the  presence  of  low  temi)erature.      In   this  respect 
putter^  has  demonstrated  in  the  leech  that  at  a  higher  tempera- 
ture, the  oxydative,  at  a  lower,  the  anoxydativc,  decomposition 
predominates.     These  are  important   facts  in  tliat  ihey  show  us 
the  superiority  of  oxydative  to  that  of  llie  anoxydativc  dismte- 
gration  in  the  cell  economy.     This  is  of  particular  interest  when 
we  consider  those  organisms  in  wliiili  great  demands  are  made 

\  A.    Putter:   "Dcr    Stoffwechscl    des   Blutcgcis    (Ilinulo   mc(licinali»   !->  I    Thril. 

Zeitschrift  fiir  allgemeine  Physiologic   Hd.   VI.   1907.      II   Ttil.  cbcrnla    IW.   VII.   1908. 


98  IRRITABILITY 

upon  the  capability  of  movement,  above  all,  in  homothermous 
forms,  the  metabolism  of  which  takes  place  on  a  continuously- 
high  level.  For  this  reason,  in  homothermous  animals  the  res- 
piration of  oxygen  is  the  almost  exclusive  source  of  energy 
production. 

The  previously  mentioned  facts  make  it  clear  that  in  one  and 
the  same  form  of  living  substance  both  oxydative  and  anoxdyative 
decomposition  processes  are  found,  depending  upon  the  condi- 
tions. This  does  not  apply  merely  to  the  individual  organic 
forms,  such  as  the  facultative  anaerobic  organisms,  but  generally 
to  all  aerobic  living  substance.  If  oxygen  is  withdrawn  from  an 
aerobic  organism  the  disintegration  does  not  cease  in  conse- 
quence. In  place  of  the  oxydative  we  have  anoxydative  decom- 
position. The  various  aerobic  organisms  are,  however,  adapted 
in  very  different  degrees  to  the  possibility  of  an  anaerobic  exist- 
ence. While  the  facultative  anaerobic  organisms  can  continue  to 
exist  without  oxygen,  the  homothermous  animals  become  asphyx- 
iated in  a  very  short  time  in  the  absence  of  oxygen,  in  that  they 
are  poisoned  by  the  products  of  the  anoxydative  decomposition, 
which  are  eliminated  with  much  more  difficulty  than  carbon 
dioxide  and  water.  The  fact,  however,  that  disintegration  also 
continues  in  an  anoxydative  form,  if  oxygen  is  withdrawn,  has 
given  rise  to  the  thought,  which  has  been  accepted  especially  by 
plant  physiologists  with  great  readiness,  that  the  decomposition 
of  organic  respiratory  substances  of  the  aerobic  organisms  inva- 
riably takes  place  in  two  stages ;  in  that  the  dextrose  molecule — to 
again  use  this  as  an  example — is  split  up  first  by  an  enzyme  into 
larger  fragments,  which  then  in  the  second  stage  of  the  process 
undergo  combustion  to  the  formation  of  carbon  dioxide  and 
water.  Such  a  possibility  cannot  be  repudiated.  I  wish,  how- 
ever, to  state  that  one  should  be  very  reluctant  in  generalization 
of  this  assumption  for  all  aerobic  organisms.  The  types  of  metab- 
olism in  the  different  organisms  are  so  manifold  and  of  such 
immense  variety  that  we  should  be  very  careful  in  our  general- 
izations before  being  in  possession  of  material  extending  over  a 
great  number  of  groups  of  organisms.  Above  all,  it  does  not 
seem  justifiable  to  also  accept  this  type  for  life  existing  at  higher 


THE  PROCESS  OF  EXCITATION'  99 

temperatures,  and  still  less  to  apply  it  to  those  instances  in  which 
the  production  of  energy   following  stimulation  is  suddenly  in- 
creased to  great  amounts.     Let  us  suppose  that  the  disintegration 
process  occurs  in  two  phases,  the  first  of  which  after  the  tyi)c  of 
the  fermentation  of  dextrose  separates  the  molecule  into  larger 
fragments,  while  in  the  second  phase  these   fragments  are  si)lit 
up  through  oxydation  into  the  formation  of  carbon  dioxide  and 
water.    We  can  then  say  with  certainty  that  in  the  first  stage  only 
a  comparatively  small  amount  of  energy  production  occurs,  for 
energy  production  by  enzymic  processes  of  this  kind   is  never 
great;  the  second  phase,  on  the  other  hand,  nui-t  l)e  a<^ociatcd 
with  a  very  considerable  energy  production,  for  by  the  addition 
of  oxygen  and  the  formation  of  carbon  dioxide  and  water  the 
strongest  affinities  possible  are  combined.     With  this  assumption 
in  certain  cases,  as,   for  instance,   in  the  sudden  production  of 
energy   in   muscle  contraction,   which   necessarily  occurs   in   the 
purely  oxydative  phase  of  the  whole  process,  the  view  is  forced 
upon  us,  that,  in  these  cases,  the  entrance  of  oxygen  into  the 
molecule  from  the  very  beginning,  even  the  first  imjxict,  i)roduces 
oxydative  decomposition  of  the  whole  molecule.     The  view  that, 
in  the  reactions  of  warm-blooded  animals,  which  occur  with  great 
rapidity   and   considerable   energy   production,    the   oxygen    pri- 
marily explosively  breaks  up  the  whole  carbon  chain,  certainly 
presents  no  more  difficulties  than  the  sui)position  that  the  sim- 
pler substances  are  attacked  secondarily,  provided  sufficient  oxy- 
gen be  present.     This  method  would  be  obviously  the  simplest. 
This  is,  however,  mere  speculation  and  a  definite  decision  between 
the    two    possibilities    cannot    be    made    at    present.      However, 
whether  the  process  takes  place  in  two  phases,  an  anoxydative 
and  an  oxydative,  or  simply  in  an  oxydative  phase,  in  any  casr. 
the  sudden  discharge  of  energy  in  the  aerobic  organism  set  free 
bv  the  stimulus,  is  brought  about  by  the  addition  of  oxygen. 

This  is  a  highly  important  fact  and  as  such  requires  the  most 
thorough  confirmation,  and  is  best  accomplished  by  the  investi- 
gation of  the  state  of  excitation  of  aerobic  substances  on  the 
withdrawal  of  oxygen.  Exi)erience  gained  by  observation  in  this 
respect  on  a  great  number  of  living  substances  shows  that  exci- 


Fig.  10. 

Rhizoplasma  kaiseri.    A— Under  normal  conditions. 
B— In  an  atmosphere  of  pure  hydrogen. 


THE  PROCESS  OF  EXCITATIOX  lui 

lability  decreases  upon  ihc  withdrawal  of  oxygen.  In  this  con- 
nection I  should  like  to  cite  some  i)articularly  significant  instances. 

During  a  sojourn  at  the  Red  Sea  in  iSD-t-'jo  1  was  able  to 
establish  this  dependence  in  the  single-celled  organism,  the  Rhizo- 
plasma  Kaiseri,  a  large  naked  orange-colored  rhizojuxl.  i  I^'igurc 
10,  A.)  Mechanical  stimulation,  which  under  normal  vital  con- 
ditions of  these  organisms  brings  about  contraction  in  the  long- 
branched  pseudopods,  becomes  ineffective  with  a  cessation  of  the 
movement  of  protoplasm,  when  oxygen  is  removed  and  is  re|)laced 
by  a  stream  of  hydrogen.  (Figure  1<>.  W.)  With  renewed  intro- 
duction of  oxygen  there  is  a  return  of  the  ijrotoi)la^mic  movement 
and  entire  recovery  takes  place. 

This  dependence  of  irritability  upon  oxygen  i^  most  clearly 
demonstrated  in  the  nerve  centers.  Vov  tliis  purpose  I  have 
employed  the  spinal  cord  of  the  frog.'  A  canula  is  introduced 
and  fixed  into  the  aorta  of  the  animal  and  the  bhjod  is  rej)laced 
by  a  current  of  oxygen-free  saline  solution.  'I'he  centers  of  tlic 
spinal  cord  are  thereby  wdiolly  isolated  from  the  supply  of  oxy- 
gen. The  indicator  for  the  irritability  here  used  is  retlex  exci- 
tation from  the  skin  to  the  gastrocnemius,  or  better,  stimulation 
of  the  central  stump  of  the  sciatic  nerve  with  single  induction 
shocks,  bringing  about  reflex  response  of  tlic  triceps.  The  retlex 
may  be  considerably  augmented  by  increasing  the  reflex  excita- 
bility of  the  spinal  cord  by  poisoning  the  animal  with  strychnine. 
On  testing  the  reflex  excitability  at  the  beginning  of  the  experi- 
ment it  will  be  found  that  the  reaction  to  each  individual  stimulus 
consists,  in  consequence  of  the  strychnine  poisoning,  of  a  long- 
continued  maximal  tetanus.  The  longer  the  deficiency  of  oxygen 
continues,  the  briefer  become  the  tetanic  reflex  contractions  fol- 
lowing a  single  stimulus.  Soon  reflex  tetanic  responses  are 
merely  short  single  contractions,  whicli  decrease  more  and  more 
with  the  continuance  of  oxygen  deficiency.  Finally,  the  same 
stimuli  which  previously  produced  strong  tetanic  contractions 
of   long   duration    are   altogether   without    efTect.      Although    by 

1  Max  Vcrworn:  "Ermiidung  ErschopfunR  und  Krh(ilv>n>{  tier  ncrv..^,i.  v  t-mrcn 
des  Riickenmarks.  Ein  Hcitrag  zur  Kt-mUiiiss  dor  I.clK-nsvorKMUgc  in  den  Ncuroncn." 
Archiv.   f.   Anat.  u.  Physiologic,  physiol.     Al)tcil.      1900  Suppl. 

The  same:    "Ermiidung  und    Erholung."      In    lUrliiu-r    Klin.    Wochcnschrift    I90I. 


102  IRRITABILITY 

increasing  the  intensity  of  stimulation  brief  contractions  can 
again  be  brought  about,  irritabiHty  decreases  more  and  more, 
until  at  last  even  the  strongest  stimuli  remain  without  result. 
If  the  oxygen-free  saline  solution  is  now  replaced  by  one  satu- 
rated with  oxygen,  or  blood  of  the  ox,  rendered  arterial,  the 
excitability  returns  within  a  few  minutes  and  soon  reaches  the 
maximal  height  which  it  possessed  under  the  influence  of  the 
strychnine  poison.  Even  the  weakest  single  stimuli  now  again 
produce  tetanus.  The  same  process  reoccurs,  if  the  fluid  used 
for  transfusion  containing  oxygen  is  again  replaced  by  an  oxygen- 
free  saline  solution.  In  this  way,  by  repeated  change  of  the  per- 
fusing fluid,  we  can  demonstrate  in  the  most  positive  manner  this 
alteration  in  irritability,  the  result  of  the  alternate  presence  and 
removal  of  oxygen.  This  is  perhaps  the  best  example  of  the 
close  dependence  of  irritability  on  oxygen. 

This  same  fact  can  be  observed  with  equal  clearness  in  the 
nerve.  At  my  suggestion  H.  v.  Baeyer^  showed  as  the  result  of 
investigations  made  in  the  Gottingen  laboratory  the  dependence 
of  irritability  of  the  nerve  upon  oxygen  for  the  first  time.  By 
employing  as  the  method  the  ascertainment  of  the  threshold  of 
stimulation  I  then  made  a  closer  study  of  the  alterations  in  irrita- 
bility during  asphyxiation.  These  observations  were  soon  after 
continued  by  Frohlichr  The  method  is  as  follows :  the  nerve  of 
a  nerve-muscle  preparation  of  the  frog  is  drawn  through  a  glass 
chamber  which  is  made  completely  air-tight  and  containing  plati- 
num electrodes.  The  air  in  the  chamber  is  then  displaced  by  a 
stream  of  pure  nitrogen.  (Figure  11.)  On  testing  that  part 
of  the  nerve  situated  within  the  glass  chamber  with  single  break 
induction  shocks  it  can  be  observed  that  its  irritability,  measured 
by  the  threshold  of  stimulation  for  muscle  contraction,  decreases 
more  and  more,  until  after  the  lapse  of  some  hours,  the  stimula- 
tion required  is  so  strong  as  to  reach  the  region  of  the  "Strom- 
schleifengrenze."  If  in  place  of  the  stream  of  nitrogen,  air  or 
pure  oxygen  is  now  allowed  to  flow  through  the  chamber,  the 

1  H.  V.  Baeyer:  "Das  Sauerstoflfbediirfniss  des  Nerven."     Zeitschrift  f.   allgemeine 
Physiologic   Bd.   II,    1903. 

2  Fr.    W.   Frohlich:  "Das   SauerstofFbediirfniss  des  Nerven."     Zeitschrift   f.  allgem. 
Physiologic  Bd.   Ill,    1904. 


THE  PROCESS  OF  EXCITATION 


1(»3 


Fig.  11. 

Arrangement  for  asphyxiating  the  nerve.  A— Gasometer  containing  pure  nitr«»g«:n.  B  and  IT  ViMili  far 
wcishing  the  gas.  C— Ether  chamber  for  eventual  experiments  with  narcosis.  D.  Di  And  K  CUm 
faucets.  F— Moist  chamber.  G— Asphyxiation  chamber.  H  and  Hi  Two  pairs  of  ckctrotScs  ovci 
which  the  nerve  is  laid.    I— Nerve  muscle  preparation. 


nerve  recovers  almost  instantaneously.  Within  the  space  of  a 
minute  its  irritability  has  risen  again  to  its  full  lici^Hit  and  the 
same  experiment,  with  the  same  result,  can  he  repeated.  I'inally, 
as  Fillie^  has  shown,  the  like  result  is  obtained  wlu-n  tlie  nerve  is 
asphyxiated  in  a  fluid  medium. 

All  these  facts,  the  number  of  which  indeed  could  be  increased 
greatly  for  other  aerobic  forms,  suffice  to  establish  tlie  fundamen- 

1  H.    Fillie:    "Studien    iibcr    die    Ersticknng    dcs    Ncrven    in    Flusigkcitcn."     Zril- 

schrift  f.  allgemeine   Physiologie,   Bd.   \III.    1908. 


104  IRRITABILITY 

tal  importance  of  oxygen  to  the  maintenance  of  irritability  of 
living  substance.  Oxygen  is  of  greatest  importance  for  a  high 
degree  of  irritability  in  all  aerobic  organisms.  All  living  systems 
which  are  characterized  by  a  great  capability  of  activity  and 
evince  strong  responses  under  the  influence  of  stimulation,  such 
as  the  vertebrates  and  insects,  are  necessarily  aerobic,  whereas 
the  living  organisms  of  pronounced  anaerobic  character,  as  some 
bacteria,  yeast  cells,  parasitic  organisms,  etc.,  manifest  on  the 
average  much  less  capability  of  activity. 

Finally,  to  briefly  summarize  the  foregoing,  the  following 
picture  presents  itself  of  disintegration  produced  by  a  momen- 
tarily acting  stimulus.  It  is  immaterial  how  the  stimulus  pro- 
duces an  excitating  effect  in  the  given  case,  whether  through 
changes  in  the  ion  concentration  of  the  living  system,  by  increase 
of  intramolecular  atomic  movement  or  in  any  other  manner,  it 
invariably  accelerates  the  disintegration  of  the  complex  mole- 
cules concerned  in  functional  metabolism,  the  nature  of  which 
varies  in  the  special  cases.  In  the  great  majority  of  instances 
nitrogen-free  organic  combinations  serve  as  material  for  the 
functional  constituent  members  of  metabolic  processes.  In  the 
anaerobic  organisms  this  decomposition  takes  place  anoxyda- 
tively  with  the  cooperation  of  enzymic  processes,  and  as  larger 
fragments  generally  result  from  the  disintegration  of  the  com- 
plex molecule,  the  production  of  energy  is  accordingly  smaller. 
The  disintegration  of  aerobic  organisms,  on  the  other  hand,  occurs 
in  the  form  of  an  oxydative  splitting  up  of  the  complex  mole- 
cules into  carbon  dioxide  and  water  so  that  the  production  of 
energy  attains  a  high  value.  The  details  concerning  the  manner 
in  which  the  individual  stages  of  this  decomposition  take  place 
and  the  interactions  by  which  its  end  products  are  reached  is 
at  present  beyond  our  knowledge.  It  would  be  a  mistake  to  gen- 
eralize in  this  connection  from  the  behavior  of  certain  groups  of 
organisms.  The  assumption  that  under  certain  conditions  the 
disintegration  occurs  in  two  phases,  the  splitting  up  resulting 
from  enzymic  action  of  the  complex  molecule  into  larger  frag- 
ments, followed  by  an  oxydative  splitting  up  of  these  into  carbon 
dioxide  and  water,  can  in  no  case  as  yet  be  justifiably  applied  to 


THE  PROCESS  OF  EXCITATIOX  103 

all  conditions  and  all  aerobic  organisms.  This  is  more  or  less  the 
impression  which  we  derive  of  the  functi(jnal  excitation  process 
as  seen  today. 

Under  normal  conditions  the  fnnctional  excitation  is  at  once 
followed  by  a  succession  of  secondary  processes,  the  "sclf- 
rcgulation  of  metabolism."  Self -regulation  after  a  functional 
excitation  is  a  fact  demonstrated  by  experience.  Hut  in  what 
manner  does  it  take  i)lacc  in  detail  ? 

As  the  functional  constituent  members  of  metaboli.sm  involve 
a  disintegration  of  the  nitrogen-free  atom  groups,  the  functional 
self-regulation  must  necessarily  furnish  in  sufficient  (juantity  and 
in  proper  form  the  carbon,  hydrogen  and  oxygen  atoms,  which 
have  been  removed  in  the  production  of  carbon  dioxide  and  water. 
This  is  accomplished,  as  is  w^ell  known,  by  the  food  and  the  intake 
of  oxygen.  It  is  of  importance  to  the  maintenance  of  living  sub- 
stance that  after  every  functional  activity  it  is  as  soon  as  possible 
again  capable  of  reaction.  Therefore,  it  is  absolutely  necessary 
that  this  material  is  in  the  proper  place,  where  building  up  is 
essential,  and  is  at  the  same  time  constantly  in  i)roper  form. 
Indeed,  the  restitution  of  the  original  state  follows  under  favor- 
able conditions  with  lightning  rapidity,  although  varying  in  dif- 
ferent forms  of  living  substance.  This  occurs  in  the  nerve  in 
an  extremely  short  time.  From  this  it  might  be  sui)posed  that 
the  living  system  by  accumulating  a  store  of  the  necessary  com- 
pensation substances  in  suitable  form,  had  made  itself  independ- 
ent to  a  certain  degree  of  the  frequently  varying  sui)ply  <^f 
material  obtained  from  the  medium. 

This  may  be  held  as  the  proper  view,  first  with  regard  lu  com- 
pensation substances.  The  fact  that  living  organisms  can  under 
some  conditions  remain  for  a  lengthened  jKTiod  in  a  state  of 
starvation,  without  losing  their  capal)ility  of  activity,  can  only 
be  explained  by  the  presence  of  a  great  quaiuity  of  reserve  sup- 
plies of  compensation  substances.  In  the  course  of  work  in  the 
laboratory  every  physiologist  has  become  accjuainted  with  the 
fact  that  frogs  which  have  been  kept  without  food  for  a  year, 
although  much  reduced  in  weight,  are  still  ca])able  of  some 
muscular  activity. 


106 


IRRITABILITY 


Organs  and  tissue,  which  are  cut  off  from  all  food  supply 
through  the  blood  and  lymph,  may  remain  active  for  many  hours. 
H.  V.  Baeyer^  has  shown  that  the  ganglion  cells  in  the  frog,  in 
which  saline  solution  was  transfused  at  room  temperature  and 


Motor  ganglia  cells  from  the  spinal  cord  of  the  frog.    A— In  normal  state. 
B— After  an  asphyxiation  leisting  8  to  9  hours.    (After  Gordon  Holmes.) 


containing  no  trace  of  organic  substances  and  where  irritability 
has  been  increased  to  the  maximal  by  means  of  strychnine,  were 
capable  of  strenuous  work  for  nine  or  ten  hours  before  losing 

1  H.  V.  Baeyer:  "Zur  Kenntniss  des  Stoffwechsels  in  den  nervosen  Centren."     Zeit- 
schr.    f.    allgem.    Physiol.    Bd.    I,    1902. 


THE  PROCESS  OE  EXCITATION 


107 


responsivity.  The  nerves  and  muscles  of  ilie  animal  retain  iheir 
excitability  for  even  a  lon^^er  period  under  the  same  conditions. 
Indeed,  we  have  histological  evidence  of  the  existence  of  or^^'anic 
reserve  material  in  the  various  cells  in  the  form  of  embedded 
bodies  in  the  protoplasm.  As  for  instance  the  disappearance  of 
the  Nissl  granules  in  the  ganglion  cells  following  great  activity.* 
(Figure  12),  or  that  of  the  granules  in  infusoria  cells  during 
starvation.-     (Eigure  13.)     We  assume  that  a  certain  amount  of 


.'M>^ 


V' 

A 

Fig. 

13. 

B 

ium  aurelia.    A— In  normal  state. 

B 

In  a  state  of  starvation 

organic  foodstuffs  in  a  state  properly  prepared  is  present  in  the 
cell.  As  the  amount  of  these  prepared  substances  is  consumed, 
new  quantities  of  stores,  having  undergone  various  preparatory 
processes,  among  which  the  enzymic  actions  may  be  considered 
to  play  a  chief  role,  are  brought  into  that  form  in  which  they 
appear  suited  to  fill  the  gap  produced  by  disintegration.  Plant 
physiologists  in  particular  have  here  again  furnished  us  with  some 

1  Gustav  Mann:  "Histological  changes  induced  in  synipatliftic  mutor  and  sensory 
nerve  cells  by  functional  activity."  In  Jcmrn.  of  Anat.  and  Physiol.  1894.  Further: 
Gordon  Holmes:  "On  morphological  changes  in  exhausted  Ranglion  cellft."  Zcit- 
schrift  f.  allgem.   Physiol.    Ed.    II,    1903. 

ZlVallcngrcn:  "Inanitionserscheinungen  der  Zdlc."  Zc-it-schrift  f.  allgrm.  Physiol. 
Bd.  I,   1902. 


108  IRRITABILITY 

essential  data  for  the  assumption  of  the  existence  of  such  pro- 
cesses which  regulate  the  transformation  of  reserve  substances 
as  well  as  its  extent.  Pfeffer^  has  found  in  several  fungi  and 
bacteria  that  there  exists  a  compensation  between  the  diastatic 
breaking  down  of  the  carbohydrates  stored  as  reserve  material 
and  the  quantity  of  dextrose  introduced.  He  further  found  that 
the  more  the  reserve  substance  is  split  up  into  dextrose  the  less 
of  the  latter  is  introduced  from  without  and  vice  versa.  De  Bary- 
some  time  ago  also  observed  in  the  bacillus  amylobacter  an  analo- 
gous relation  between  the  enzymatic  cellular  digestion  and  the 
quantity  of  dextrose  introduced  with  the  food.  An  equilibrium, 
therefore,  exists  between  the  required  amount  of  dextrose  and 
the  extent  of  enzymic  splitting  up  processes  of  the  reserve  mate- 
rial. A  great  number  of  similar  processes  have  been  observed. 
Even  though  the  details  of  the  whole  preparatory  assimilative 
processes  are  beyond  our  knowledge  we  can  still  say  with  certainty 
that,  on  the  one  hand,  everywhere  great  quantities  of  organic 
reserve  substances  are  always  present  in  the  cell,  and  on  the  other, 
that  these  substances  are  subjected  to  a  transformation  into  suit- 
able material  for  building-up  processes,  the  extent  of  which  is 
controlled  according  to  need,  by  the  processes  of  self-regulation. 
Entirely  different  is  the  question  if  the  cell  also  possesses  a 
reserve  store  of  oxygen.  In  this  respect  views  have  widely 
differed,  and  even  today  no  conformity  of  opinions  has  been 
arrived  at.  The  fact  that  many  purely  aerobic  organisms  and  tis- 
sues can  exist  under  complete  exclusion  of  oxygen  for  a  longer 
or  shorter  period,  retaining  their  excitability  and  producing  car- 
bon dioxide,  has  for  a  long  time  led  a  great  number  of  investi- 
gators, such  as  Liebig,  Matteucci,  Engelmann,  Pettenkofer  and 
Voit,  Claude  Bernard,  Verworn,  H.  v.  Baeyer  and  others,  to  the 
supposition  that  a  reserve  store  of  oxygen  must  exist  in  the  living 
substance  which  maintains  its  excitability  for  a  time.  More 
recent  information,  however,  of  the  transition  of  the  oxydative 
to  the  anoxydative  disintegration  under  a  deficiency  of  oxygen, 

1  W.  Pfeffer:  "Ueber  die  regulatorische  Bildung  von  Diastase."     In  der  math.  phys. 
Klasse  d.  Konigl.  Sachs  Ges.  d.  Wiss.  zu  Leipzig  1896. 

2  De   Bary:   "Sur   la    fermentation   de   la   cellulose."      In    Bull,    de   la    Soc.    hot.    de 
France   1879. 


THE  PROCESS  OF  EXCITATION  109 

as  can  be  observed  in  plants  and  certain  invertebrate  animals, 
indicates  that  here  also  there  is  the  p(jssibility  of  another  expla- 
nation of  these  facts.  V^arious  attem|)ts  have  !)een  made  to  solve 
the  problem  if  reserve  oxygen  is  present  in  the  cell  or  not.  The 
experiments  of  Rosenthal,^  carried  out  with  his  respiration  calo- 
rimeter, seemed  to  point  directly  to  an  oxygen  reserve  in  the 
organism  of  the  mammal.  He  observed  that  during  respiration  in 
an  atmosphere  rich  in  oxygen  the  respiratory  quotient  (CO,  lO,) 
became  lower  than  in  ordinary  air,  that  is,  that  oxygen,  and  that 
indeed  in  considerable  quantity,  must  be  retained  in  the  organism. 
Nevertheless  Falloisc-  found  that  when  rabbits,  which  had  been 
kept  in  an  atmosphere  containing  80  per  cent  of  oxygen,  were 
asphyxiated,  the  time  necessary  to  produce  death  was  no  longer 
than  in  animals  which  had  been  kept  previously  in  ordinary  air. 
The  correctness  of  the  observations  of  Rosenthal  have  been  dis- 
puted by  Durig.^  PVinterstein*  also,  employing  the  microrespira- 
tion  methods  of  Thunberg  upon  the  spinal  cord  of  the  frog, 
believed  that  he  had  found  proof  that  an  oxygen  reserve  cannot 
take  place.  He  reasoned  thus:  If  the  cells  of  the  spinal  cord 
contain  reserve  oxygen,  which  is  used  up  when  pure  nitrogen  only 
is  breathed,  then  it  necessarily  follows  that  after  reintroduction 
of  oxygen,  following  asphyxiation,  a  detinite  quantity  must  be 
stored  up  again  as  reserve.  In  consequence,  the  respiratory 
quotient  following  the  intake  of  oxygen  after  asphyxiation  should 
be  smaller  than  when  the  animal  is  in  air.  He  found,  however. 
that  the  respiratory  quotient  does  not  essentially  change  and  con- 
cluded from  this  that  storage  of  oxygen  does  not  take  place. 
In  these  experiments,  however,  there  exists  no  certain  indicator 
as  to  the  state  of  the  spinal  cord  during  asphyxiation  and  recovery 
in  the  given  case.     The  spinal  cord  may  be  severely  injured  and 

1  Rosenthal:  "Untersuchungen  iiber  den  respiratorischcn  Stoffwcchscl."  Arch.  f. 
Anat.   u.    Physiologic   physiolog.   Abt.    1902   und   Suppl.    1902. 

2  Falloise:  "Influence  de  la  respiration  d'une  atmosphere  suroxygenc  »ur  I'tbtorp- 
tion  d'o-xygene."     Traveaux  du  laborat.  de  physiol.  de  L.  Frederic  LicKe.  T.  VI. 

ZDurig:  "Ueber  Aufnahme  und  Verbrauch  von  Sauerstoff  bei  -'Xendcrung  Mrinet 
Partialdruckes  in  der  Alveolarluft."  Arch.  f.  Anat.  u.  Physiol,  physiol.  Abt.  1903 
Suppl. 

4,  IVinterstein :  "Ueber  den   Mechanismus  der  Gcwcbeatmung."     Zcitschr.   f.  allijcra. 

Physiol.   Bd.  VI,   1907. 


110  IRRITABILITY 

even  undergo  degeneration  during  asphyxiation,  and  the  recovery 
following  the  reintroduction  of  oxygen  may  be  either  incomplete 
or  nil,  without  there  being  a  method  for  its  determination.  Apart 
from  this,  Lesser^  has  already  emphasized,  in  opposition  to  these 
experiments,  that  the  respiratory  quotient  in  recovery  is  no  crite- 
rion to  guide  us.  It  is  immaterial  whether  during  asphyxiation 
oxygen  respiration  occurs  following  a  reserve  supply,  or  that 
an  anoxydative  formation  of  carbon  dioxide  has  taken  place, 
for  in  both  instances  the  respiratory  quotient  would  be  less  after 
asphyxiation  when  there  is  again  an  oxygen  supply.  It  is,  there- 
fore, quite  impossible  to  decide  the  question  by  the  employment 
of  this  method.  For  this  reason  Lesser  has  attempted  to  solve 
the  problem  by  means  of  quite  another  method,  and  was  con- 
vinced that  he  had  refuted  finally  the  belief  in  the  existence  of 
reserve  oxygen.  His  method  consists  in  the  employment  of  the 
Bunsen  ice  calorimeter,  by  which  he  determines  the  heat  pro- 
duction of  frogs,  kept  first  in  air,  then  in  nitrogen,  and  at  the 
end  of  each  experiment  ascertaining  the  amount  of  output  of 
carbon  dioxide,  respectively  in  air  and  nitrogen.  He  found  that 
the  quantity  of  heat,  calculated  in  terms  of  100  grms.  body 
weight  per  hour,  produced  in  nitrogen  was  considerably  less  than 
that  under  corresponding  conditions  in  air,  but  that  the  produc- 
tion of  carbon  dioxide,  on  the  other  hand,  during  the  first  hours  in 
nitrogen  was  doubled  in  amount,  as  compared  to  that  in  air. 
From  this  he  concludes  that  the  carbon  dioxide  formation  in 
nitrogen  must  be  different  from  that  in  air,  as  it  is  associated 
with  a  reduced  heat  production.  In  other  words,  carbon  dioxide 
formation,  while  the  animal  is  in  a  nitrogen  atmosphere,  does  not 
have  its  origin  in  oxydative  processes  at  the  cost  of  stored  up 
oxygen.  I  regret  that  I  am  unable  to  accept  these  arguments  as 
conclusive  evidence  against  the  assumption  of  an  oxygen  re- 
serve, as  this  question  cannot  be  decided  by  the  use  of  such 
methods.  Lesser  does  not  measure  the  amount  of  carbon  dioxide 
until  the  end  of  his  experiments,  that  is,  he  learns  merely  the 

1  Lesser:  "Die  Warmeabgabe  der  Frosche  in  Luft  und  sauerstofffreien  Medien. 
Ein  experimenteller  Beweis  dass  die  COj  Production  der  Frosche  im  sauerstofffreien 
Raum  nicht  auf  Kosten  gespeicherten  Sauerstoffs  geschieht."  Zeitschr.  f.  Biologie 
Bd.   51,    1908. 


THE  PROCESS  OF  EXCITATION  ill 

entire  carbon  dioxide  production  during  a  period  of  many  hours. 
No  conclusions  can  be  drawn  from  this  as  to  ilic  conditions 
existing  in  the  first  period  of  time,  chrcclly  after  the  animals 
have  been  subjected  to  an  atmosj)lierc  of  nitrof^cn.  It  is  (juitc 
possible  that  subsequent  to  the  ciiange  to  nitrogen  an  oxydative 
carbon  dioxide  formation  may  have  continued  in  decreasing 
degree,  without  this  being  shown  in  the  final  result.  The  i)rob- 
lem  of  the  existence  of  a  reserve  sui)ply  of  oxygen  is  in  no  way 
solved  by  these  experiments. 

In  assuming  the  presence  of  a  reserve  supply  of  oxygen  in  the 
cell  we  must  above  all  entertain  no  false  conception  as  to  its 
amount.  This  must  be,  as  I  have  often  had  occasion  to  empha- 
size, exceedingly  small  and  in  no  way  comparable  with  the  great 
masses  of  organic  reserve  substances  contained  in  the  cell.  The 
assumption,  especially  for  the  nerve  centers  of  the  frog,  that  the 
excitability  remains  after  complete  exclusion  of  oxygen  must  be 
looked  upon  as  demonstrating  a  reserve  supply  of  oxygen,  would 
oblige  one  to  suppose  the  presence  of  such  a  small  store  of  oxygen 
that  it  would  be  completely  exhausted  by  continued  activity  in 
room  temperature  within  ten  to  twenty-five  minutes.  Strych- 
ninized  frogs,  in  which  the  blood  has  been  replaced  by  an  oxygen- 
free  saline  solution,  lose,  as  I  have  shown, ^  their  excitability  com- 
pletely within  ten  to  twenty-five  minutes  after  the  blood  has 
been  displaced.  Nevertheless  the  assumption  of  the  existence  of 
a  small  oxygen  supply  in  the  cell  can  hardly  be  evaded.  It  must 
not  be  imagined  that  the  moment  the  blood  of  the  frog  has  l)ecn 
replaced  with  an  oxygen-free  solution,  there  is  not  a  trace  of 
oxygen  left  in  the  organism.  Were  such  the  case,  the  irritability, 
if  measured  by  the  extent  of  the  response,  would  sink  momenta- 
rily to  a  very  low  level,  for  the  anoxydative  disintegration  pro- 
cesses are  associated  with  an  incomparably  smaller  production  of 
energy  than  those  of  oxydative  disintegration.  We  sec,  however, 
that  the  irritability  in  the  muscles,  nerves  and  nerve  centers  of  the 
frog  even  after  the  complete  withdrawal  of  oxygen  at  first  re- 
mains practically  at  the  former  height  and  only  very  gradually 

\Max  Verworn:  "Ermudung,  Ersch6pfung  und   Krholung  der  ncrvoncn  Centra  dc« 
Ruchenmarks."     Arch.   f.   Anat.   u.    Physiol,    physiol.    Abt.    Suppl.    1900. 


112  IRRITABILITY 

decreases.  Above  all  it  would  seem  to  me  to  be  in  the  interest 
of  the  preservation  of  the  organism  and  especially  of  those  parts 
in  which  there  is  a  high  energy  production  and  particularly  those 
substances  in  which  energy  production  predominates,  that  the 
material  necessary  for  its  formation  is  always  at  its  disposal  in 
sufficient  quantity.  Otherwise  the  capability  of  action  of  the 
organism  would  be  impaired  at  every  moment  or  at  least  suffer 
great  fluctuations. 

In  accordance  with  this  we  must  suppose  that  under  physiologi- 
cal conditions  all  those  substances  required  to  replace  the  disin- 
tegrated molecules  are  always  present  in  the  cell  in  sufficient 
quantity  and  suitable  form  to  replace  at  once  those  lost  by  exci- 
tation. Further,  without  doubt,  in  the  organism  which  is  always 
aerobic,  oxygen  must  be  present  in  certain  quantities  to  assure  at 
any  moment  oxygen  replacement  following  oxydative  disinte- 
gration, to  guarantee  sufficient  amount  for  succeeding  stimulation. 

A  further  question  arises :  How  is  it  that  the  material  lost 
in  disintegration  is  always  replaced  in  just  sufficient  quantity 
to  establish  the  metabolic  equilibrium?  In  short,  how  are  we 
to  understand  in  a  mechanical  sense  the  self-regulation  of 
metabolism  ? 

In  the  preservation  of  metabolic  equilibrium,  we  have  a  pro- 
cess before  us,  the  principle  of  which  is  nowadays  restricted  to 
living  substance.  In  my  ''Biogen  hypothesis,"^  I  have  associated 
the  self-regulation  of  metabolism  with  the  chemical  equilibrium 
in  interreacting  masses.  I  have  considered  the  metabolic  self- 
regulation  as  the  expression  of  the  formation  of  a  mass  equilib- 
rium between  the  quantity  of  foodstuffs  and  the  quantity  of  a 
hypothetical  combination  of  living  substance,  the  hiogen,  which 
continuously  disintegrates  and  builds  up  again  of  its  own  accord. 
In  fact,  however,  we  have  in  the  chemical  equilibrium  of  reacting 
mixtures  in  the  non-living  world,  a  principle  which  is  completely 
analogous  to  the  self-regulation  in  living  substance.  The  chemical 
facts  are,  indeed,  well  known.  If  we  take  the  classical  example 
of   the   formation  of   ethylacetat   from   acetic   acid   and  alcohol, 

1  Max  Verworn:  "Die  Biogenhypothese."  Jena  1903.  Compare  also  Max  Verworn: 
Allgemeine  Physiologic  V.  Aufl.  Jena   1909. 


THE  PROCESS  OF  EXCITATION  113 

we  have  a  case  of  an  inanimate  system,  in  which  tlic  amounts  of 
the  reacting  substances  are  in  constant  e(|uihhrium.  Tlic  reaction 
following  the  mixture  of  equal  amounts  of  alcohol  and  acetic  acid 

is  as  follows: 

Yi  Mol.   C,HpH  +/3  Mol.  CH,C()OH 
=  yz  Mol.  CH3CO0C,H,  +  23  Mol.  II,(). 

In  this  reaction  there  is  an  alteration  only  in  the  ah'^olute 
quantity  of  the  individual  constituents  but  never  in  the  relative 
amount.  In  the  living  system  we  have  a  completely  analogous 
instance,  which  apart  from  its  course  differs  from  the  inanimate 
example  merely  in  the  following  points:  In  the  first  i)lace.  certain 
quantities  of  substances  reacting  on  each  ollu-r  are  continually 
introduced  into  and  certain  reaction  i)roducts  continually  re- 
moved from  the  living  system.  Secondly,  the  reacting  mixture 
of  the  living  substance  is  not  homogeneous,  and  at  the  s«'ime 
time  is  more  complicated  than  that  of  the  inanimate  example. 
Thirdly,  the  sum  total  of  the  reaction  is  not  reversible  in  its  en- 
tirety. The  question  arises,  should  any  essential  ditTcrencc 
between  metabolic  self-regulation  and  the  maintenance  of  chemi- 
cal equilibrium  be  assumed  upon  this  statement?  I  must  con- 
fess that  this  does  not  appear  to  me  to  be  the  case.  Tlic  fact 
that  organisms  exist  in  a  stream  of  substances  by  which  tlieir 
nutrition  is  introduced  and  the  metabolic  ])roducts  removed, 
cannot  have  any  influence  on  the  state  of  ecjuilibrium  so  long  as 
the  conditions  are  again  and  again  replaced  in  the  same  manner. 
The  equilibrium  can  only  be  influenced  when  the  introduction  of 
foodstuffs  or  the  output  of  metabolic  products  is  changed  in  value. 
Then  they  occur  as  the  inanimate  example,  when  various  amounts 
of  material  are  brought  together.  A  new  eciuilihrium  takes  place, 
having  a  higher  or  a  lower  mass  level.  This  is  also  true  in  the 
living  substance,  in  growth  and  in  atroi)hy.  The  ecjuilibrium  is 
disturbed  as  happens  in  the  inanimate  reacting  mixture,  where 
different  quantities  of  reacting  substances  are  brought  together. 
In  both  instances  we  have  in  principle  a  conformity  of  behavior 
of  the  inanimate  and  the  living  system.  Secondly,  as  far  as  the 
greater  complexity  and  inhomogeneity  of  the  living  reacting  mix- 


114  IRRITABILITY 

ture  is  concerned,  it  is  self-evident  that  this  Hkewise  does  not 
constitute  an  essential  difference,  for  we  are  acquainted  with  con- 
ditions of  equilibrium  in  chemical  reactions  possessing  a  number 
of  members  and  in  inhomogeneous  mixtures.  Finally,  the  fact 
that  the  reaction  in  the  living  system  is  not  totally  reversible, 
forms  no  barrier  to  the  assumption  in  principle  of  metabolic  self- 
regulation  as  a  chemical  equilibrium.  It  is  quite  possible  to  con- 
ceive of  a  chemical  equilibrium  in  a  reacting  mixture,  of  which 
only  certain  constituent  processes  are  reversible,  without  the 
totality  of  the  reactions  as  a  whole  being  necessarily  so.  Let  us 
assume,  by  way  of  example,  that  the  assimilative  processes  of 
the  metabolic  chain  are  reversible,  then  under  constant  quantita- 
tive relations  of  foodstuffs,  following  every  disintegration  of 
assimilative  products  with  removal  of  the  decomposition  products, 
the  same  amount  of  assimilatory  processes  is  required  for  build- 
ing up.  And  this  is  just  that  which  we  observe  in  metabolic 
equilibrium.  Accordingly,  we  may  look  upon  the  metabolic  equi- 
librium as  a  special,  although  a  very  highly  complicated,  instance 
of  chemical  equilibrium,  and  we  may  explain  the  metabolic  self- 
regulation  following  a  dissimilative  excitation  of  the  same,  by 
those  principles  on  which  the  rebuilding  of  chemical  equilibrium 
is  founded.  It  is  true  that  the  special  details  of  this  process  can 
be  differentiated  in  only  that  degree  in  which  it  is  possible  to 
penetrate  at  all  into  the  details  of  metabolism  of  the  given  cell 
form.    In  this,  as  is  well  known,  the  advance  is  extremely  slow. 

The  rebuilding  process  following  decomposition  of  living  sub- 
stance in  response  to  an  excitating  stimulus  consists  not  merely 
in  compensation  for  the  decomposed  atom  groups  but  also  in  the 
removal  of  disintegration  products.  This  removal  can  be  accom- 
plished, in  so  far  as  simple  chemical  substances  such  as  carbon 
dioxide  and  water  are  concerned,  by  diffusion.  Observations 
have  shown  that  the  semi-permeable  protoplasm  surface  is  per- 
vious to  water  and  carbon  dioxide.  The  latter  can,  therefore, 
depending  upon  the  amount  of  concentration,  be  eliminated  from 
the  living  substance.  Output  of  water  likewise  takes  place  in  so 
far  as  the  specific  water  content  of  the  living  substance  is  ex- 
ceeded and  which  is  osmotically  regulated  by  its  amount  of  salt 


THE  PROCESS  OF  EXCITATIOX  115 

content.  \Mien,  finally,  osmotic  pressure  wiiliin  the  living  cell 
and  in  the  surrounding  medium  is  equal,  the  interchange  of  water 
ceases.  All  these  processes  are  exi)lained  by  dilTusion.  Self- 
regulation  takes  place  in  this  regard  simply  by  osmotic  means. 
The  conditions  in  respect  to  those  decomjKjsition  products  con- 
sisting in  more  complicated  organic  combinations,  such  as  lactic 
acid,  fatty  acids  and  nitrogen  derivatives  of  protein  disintegration, 
are  somewhat  different  in  that  the  protoi)lasm  surface  possesses 
the  property  of  hindering  the  passage  of  these  substances  into  the 
medium.  These  are,  as  is  well  known,  first  transformed  by  sec- 
ondary chemical  processes  into  transfusable  substances.  In  this 
transference  the  oxydative  decomposition  with  the  formation  of 
simpler  substances  plays  the  most  important  role,  so  that  the  sub- 
stances thereby  formed,  namely,  carbon  dioxide,  water  and 
ammonia,  are  osmotically  eliminated  as  the  result  of  the  selective 
permeability  of  the  surface  of  the  protoplasm.  In  thi>  way  the 
living  cell  rids  itself  of  the  useless  products  of  metabolism. 

Finally,  the  question  remains,  is  the  original  state,  as  it  existed 
before  the  influence  of  the  stimulus,  really  completely  recovered 
by  metabolic  self-regulation,  or  does  even  individual  excitation  of 
brief  duration  produce  a  continued  change  in  the  protoj^lasm  ?  It 
is  quite  impossible  to  prove  that  such  an  effect  follows  the  momen- 
tarily acting  single  stimulus,  if  stimulation  has  not  exceeded  the 
physiological  limits  of  intensity.  Should  it  exist,  it  must  be 
imperceptible.  Nevertheless,  it  ought  to  be  i)ossible  by  fre(iuently 
repeated  application  of  the  stimulus  to  increase  this  which  is 
imperceptible  to  an  extent  in  which  it  is  perceptible.  This  is, 
indeed,  the  case  and  is  manifested  as  we  have  already  seen  in 
the  increase  of  the  volume  of  living  substance  by  fre(]uently 
recurring  functional  excitation.  We  can,  therefore,  assume  with 
great  probability  that  even  the  momentarily  acting  individual 
stimulus  produces,  although  not  perceptible  per  sc.  lasting  ctTect 
in  the  cell.  The  functional  excitation  must  be  followed  sec- 
ondarily by  an  increase  of  the  assimilative  phase  of  the  entire 
cytoplastic  metabolism.  Otherw^ise  the  taking  place  of  the  in- 
crease of  volume  of  the  living  system  following  frequent  excita- 
tion  of    the    functional    constituent    members    of    metabolism,    is 


116  IRRITABILITY 

unintelligible.      But   how   are   we   to   interpret   these   secondary 
results  from  a  physical  standpoint?    First  of  all,  it  must  be  stated 
that  we  do  not  know  of  such  hypertrophy  following  activity  in 
unicellular  organisms,  but  only  in  the  tissues  and  organs  of  multi- 
cellular forms,  in  muscles,  nerve  cells,  glands,  etc.     In  the  cell 
community  of  the  vertebrates,  however,  the  studies  on  the  rela- 
tions between  activity  and  the  blood  supply  of  the  particular 
tissue  or  organ  furnish  a  physical  interpretation  for  the  exist- 
ence of  the  functional  hypertrophy.     The  active  portions  show 
a  dilation  of  the  blood  vessels,  therefore  an  increased  supply  of 
blood  and  consequently  an  increase  in  the  circulation  of  lymph. 
In  other  words:  the  supply  of  nourishment  to  the  individual  cell 
and  the  removal  of  the  metabolic  products  in  a  unit  of  time  is 
increased.     The  preceding  discussion  of  the  dependence  of  the 
conditions  of  equilibrium  upon  the  quantitative  relations  of  the 
reacting  substances  makes  it  clear  that  under  these  conditions  a 
metabolic  equilibrium  on  a  higher  quantitative  level  must  occur; 
that  is,  the  living  substance  must  increase  in  amount  just  as  in 
the  inanimate  example  the  absolute  amount  of  the  aethylacetat 
increases  if  more  alcohol  and  acetic  acid  are  introduced  to  an 
equal  degree.     Some  time  ago^  I  expressed  the  opinion  that  the 
increase  of  the  blood  supply  in  a  functionally  active  organ  must 
be  based  on  a  physical  self-regulation,  which  takes  place  as  a 
result   of   the   fact  that  metabolic   products   of  the   tissue   cells 
influence  the  cells  of  the  vessel  walls  in  that  part,  so  that  the 
vessels  dilate  and  more  lymph  is  formed.     In  the  meantime  this 
has  been  proved  to  be  indeed  the  case.    Schwarz  und  Lemherger^ 
and  Ishikawa^  have  shown  that  especially  the  weak  acids,  which 
are  produced  in  larger  amount  as  a  result  of  strong  activity  of  the 
cells,  bring  about  vessels'  dilation.     By  the  demonstration  of  this 
highly  important  process  of  self-regulation  the  last  link  has  been 
added    for   the   physical   understanding   of    the    hypertrophy    of 
activity  of  the  tissue  cells  by   continued   functional   excitation. 

1  Max  Verworn:  "Die  cellularphysiologische  Grundlage  des  Gedachtnisses."  Zeitschr. 
f.  allgem.   Physiol.   Bd.  VI,   1907. 

2  Schwarz    und    Leniherger :    "Uber    die    Wirkung    Kleinster    Sauremengen    auf    die 
Blutgefiisse."     Pfliigers  Arch.  Bd.   141,   1911. 

3  These   investigations  have  not  yet  been   published. 


THE  PROCESS  OF  EXCITATION  117 

Whether  or  not  the  same  ai)i)lics  to  the  single  hving  cell,  if  the 
unicellular  organism  likewise  undcrgcK's  a  (juantilative  increase 
by  a  continuous  functional  excitation,  and  if  the  single  cell  |>os- 
sesses  in  itself  a  corresponding  mechanism  of  self-regulation 
similar  to  the  cell  community  in  the  vertebrates,  cannot  I>c 
answered,  for  concerning  all  these  ])r()l)lems  information  is  lack- 
ing for  the  present. 


CHAPTER   VI 

CONDUCTIVITY 


Contents:  Only  processes  of  excitation  are  conducted,  not  processes  of 
depression.  Conduction  of  excitation  in  its  two  extreme  instances. 
Conduction  in  undififerentiated  pseudopod  protoplasm  of  rhizopoda. 
Conduction  of  excitation  with  decrement  of  intensity  and  rapidity. 
Conduction  of  excitation  in  the  nerve.  Rapidity  of  conduction  of 
excitation  without  decrement.  Relation  between  irritability  and  con- 
ductivity. Conduction  of  excitation  with  decrement  of  the  nerve  after 
artificial  depression  of  irritability  by  narcosis.  Theory  of  the  decre- 
mentless  conduction  of  the  normal  nerve.  Proof  of  the  validity  of 
the  "all  or  none  law"  in  the  medullated  nerve.  Theory  of  the  process 
of  the  conductivity  of  excitation.  Theory  of  core  model  (Kernleiter). 
Electrochemical  theory  of  conduction  based  on  the  properties  of  semi- 
permeable surfaces. 

When  the  response  to  a  stimulus  is  studied  in  a  living  system, 
whether  it  be  a  single  cell,  a  tissue,  or  a  complex  organism,  the 
indicator  used,  either  that  of  movement,  current  of  action,  pro- 
duction of  certain  substances,  the  development  of  Hght,  of  heat 
or  the  alteration  of  form,  is  the  result  of  two  distinct  processes. 
The  first  of  these  is  primary  excitation,  brought  about  by  the 
stimulus  at  a  local  point,  and  the  second  is  an  extension  of  the 
excitation  to  the  surrounding  tissue.  We  are  not  in  a  position 
to  experimentally  bring  about  a  response  to  stimulation,  in  which 
the  primary  excitation  occurs  and  not  the  secondary  process, 
that  of  conductivity.  All  living  substance  contains  this  property, 
although  to  a  very  different  degree,  as  all  living  substance  pos- 
sesses irritability,  and  this  presents  the  condition  not  only  for 
the  taking  place  of  the  process  of  excitation  but  also  that  of  its 
conduction. 

If  I  here  speak  only  specifically  of  the  conduction  of  excitation 
instead  of  the  conductivity  of  response  to  stimulation  this  is  not 


CONDUCTIVITY  119 

only  primarily  for  the  reason  lliat  we  intend  especially  to  analyze 
the  conductivity  of  excitation  on  this  occasion,  but  also  because 
no  other  effects  of  stimulation  except  those  of  excitation  can  l>e 
conducted  from  the  part  affected  by  the  stimulus  to  the  sur- 
roundings. 

Although  considered  on  theoretical  grounds  it  appears  more 
or  less  improbable  that  depression  is  extended  from  the  place  of 
its  origin,  it  is  very  easy  to  convince  one's  self  experimcnlallv  of 
the  fact  that  depression  following  a  stimulus  is  invariably  local- 
ized to  that  portion  directly  affected  by  the  stimulus.  The  nerve 
furnishes  a  very  favorable  object  for  this  purpose.  If  a  nerve 
muscle  preparation  of  the  frog  is  made  and  introduced  in  the 
glass  chamber  previously  described  containing  platinum  elec- 
trodes, and  another  pair  is  applied  to  the  nerve  between  the  cham- 
ber and  the  muscle,  it  is  possible  to  subject  the  stretch  of  nerve  in 
the  chamber  to  various  agents,  producing  a  paralyzing  etTect.  In 
this  way  it  may  be  exposed  to  an  atmosphere  of  pure  nitrogen 
for  example,  or  to  narcosis  as  by  ether,  chloroform,  carbon  diox- 
ide and  other  gases,  to  an  increase  in  temperature  or  to  other 
agents,  without  these  in  any  w^ay  affecting  the  irritability  of  the 
nerve  stretch  situated  over  the  electrode  between  the  chamber 
and  the  muscle.  The  contractions  of  the  muscle,  which  are  pro- 
duced by  stimulation  of  the  periphery  region  of  the  nerve  with 
stimuli  of  a  definite  strength,  remain  unaltered,  even  when  the 
asphyxiated  stretch  of  nerve  in  the  chamber  is  already  completely 
degenerated.  The  central  depression  of  a  gangliun  cell  «»f  a 
motory  neuron  is  likew^ise  wholly  without  influence  on  the  degree 
of  excitability  of  its  nerve  fiber,  as  I  was  able  to  demonstrate* 
in  the  reflex  inhibition  of  the  motor  neurons  of  the  si)inal  cord 
of  the  dog.  (Figure  14.)  That  which  is  conducted  by  the 
nerves  is  solely  the  process  of  excitation. 

It  is  our  task  to  analyze  in  detail  the  conditions  involved  in  the 
conduction  of  excitation  in  order  to  obtain  a  deeper  insight  into 
the  physics  of  this  process.  A  comparative  survey  of  a  .series  of 
various  types  of  living  substance  shows  us  that   they  differ  in 

1  Max  I'crworn:  "Zur  Physiologic  der  nervoscn  Hcmmungs«rschcinungcn."    Arch.  f. 

Anat.  u.  Physiol,  physiol.  Abt.  Suppl.    1900. 


IRRITABILITY 


Fig.  14. 

Contractions  of  the  musculus  extensor  digitorum  communis  longus  of  the  dog,  brought  about  by  rhyth- 
mic stimulation  of  the  nervus  peroneus.  The  muscle  is  in  the  condition  of  tonic  excitation  which 
proceeds  from  the  center.  The  <utows  indicate  the  point  where  reflex  inhibition  of  the  central  tonus 
is  produced.    The  height  of  the  single  contraction  undergoes  no  diminution. 


respect  to  the  conduction  of  excitation  in  the  following  points : 
In  regard  to  the  rapidity  with  which  the  excitation  is  conducted, 
the  extent  of  the  area  over  which  it  spreads,  and  the  intensity 
with  which  it  extends.  These  conditions  may  be  best  illustrated 
by  citing  two  extreme  examples.  The  one  is  formed  by  the 
rhizopods,  the  other  by  the  nerve  fibers.  Between  these  two 
extremes  we  have  manifold  gradations  in  the  conditions  of  con- 
ductivity. Not  all  cell  forms  are  suitable  objects  for  the  study  of 
conductivity.  There  are  forms  of  rhizopods  which  are  as  favor- 
able to  investigation  as  the  nerve;  this  is  due  to  the  fact  that, 


CONDUCTIMTV  121 

although  they  are  often  of  microscopic  dimensions,  they  ix)ssess 
elongated  fingerlike  or  threadlike  pseudopods. 

Indeed,  a  rhizopod  cell,  with  its  straight,  elongated  pseudcjpods, 
is  preeminently  fitted  as  an  object  of  comparison  with  a  neuron. 
Although  the  difiference  in  respect  to  the  individual  points  is  so 
far-reaching,  still,  based  on  their  outward  morphological  similarity 
various  physiological  parallels  in  both  are  forced  on  our  observa- 
tion. A  comparison  of  the  rhizopod  cell  with  the  neuron  can 
consequently  guard  us  from  many  erroneous  generalizations 
which  we  might  be  inclined  to  deduce  from  a  one-sided  investi- 
gation of  the  nerve.  This  is  especially  the  case  in  regard  to  the 
conductivity  of  excitation,  which  was  formerly  studied  almost 
exclusively  on  the  nerve  and  only  occasionally  on  the  muscle, 
which  offers  similar  conditions.  The  nerve,  in  which  the  func- 
tion of  the  conductivity  of  excitation  is  particularly  highly  devel- 
oped, was  considered  at  the  same  time  as  the  tyi)e  in  which  this 
process  could  be  most  readily  analyzed,  and  from  which  it  was 
believed  general  information  of  the  process  of  the  conductivity  of 
excitation  could  first  be  gained.  This  view  has  led  to  seriou> 
errors,  as  the  nerve,  resulting  from  the  high  development  of  its 
conductive  capability,  shows  quite  one-sided  si)ecialized  conditions, 
which  can  by  no  means  be  transferred  to  other  forms  of  living 
substance. 

A  very  suitable  object  among  rhizopods  for  the  study  of  con- 
ductivity, and  which  is  everywhere  easily  procured,  is  Difflinjia. 
This  species  living  in  small  pools  has  a  delicate  urn-sha{>ed.  pear- 
shaped  or  flask-shaped  capsule  built  up  of  sand  grains,  diatomes 
or  material  produced  by  the  organism  itself.  hVom  the  oj)ening 
the  protoplasm  extends  often  to  a  considerable  length  its  finger- 
shaped  hyaline  pseudopods.  When  Difflugia  is  placed  in  a  flat 
dish  in  water  and  observed  under  the  microscoi)e.  it  is  frequently 
seen  to  extend  from  the  opening  long  i)seudopods  in  exactly  oppo- 
site directions,  which  reach  for  a  considerable  distance  on  the 
bottom.  These  offer  particularly  favorable  conditions  for  the 
study  of  the  conduction  of  excitation.  When  this  animal  is 
placed  under  a  microscope,  the  i)seudopods  are  very  readily  stim- 
ulated at  any  position  to  a  desired  extent  by  means  of  a  sharp 


122  IRRITABILITY 

needle,  to  which  fat  has  been  previously  applied  and  subse- 
quently the  excess  removed.  The  extension  of  the  response 
from  one  point  toward  the  other  can  then  be  followed  with 
great  ease.  The  pseudopod  of  the  rhizopod  has  the  great  advan- 
tage over  the  nerve  that  its  excitation  can  be  directly  observed. 
The  excitation  following  weaker  stimulation  is  manifested  by 
a  wrinkling  of  the  previously  completely  smooth  surface ;  stronger 
stimulation  produces  differentiation  of  the  hyaline  protoplasm  to 
a  strongly  refractive  strand  in  the  axis  and  a  turbid  myelinlike 
mass  at  the  periphery,  the  pseudopod  at  the  same  time  retracting 
toward  the  central  cell  body.  In  spite  of  all  these  occurrences 
being  of  microscopic  dimensions,  still  with  some  practice  it  is 
quite  possible  to  experiment  on  them  under  the  microscope.  In 
this  way  I  found  it  comparatively  simple  to  study  the  fundamental 
principles  of  conductivity. 

All  these  factors,  the  intensity  with  which  the  excitation 
extends  from  the  point  of  stimulation,  the  rapidity  of  the  exten- 
sion, and  finally  the  area  over  which  conduction  takes  place,  are 
manifestations  of  the  intensity  of  stimulus,  and  as  such  alter 
with  these  in  corresponding  manner.  If  the  end  of  a  pseudopod 
is  barely  touched  and  thereby  weakly  stimulated,  the  response  is 
restricted  to  a  slight  wrinkling  of  the  surface,  which  slowly  ex- 
tends to  the  immediate  neighborhood,  whilst  the  more  distant 
parts  of  the  pseudopod  are  not  affected  at  all  by  the  excitation. 
(Figure  15,  A.)  On  a  stronger  stimulation  of  the  pseudopod  by 
slight  pressure,  the  response  is  likewise  stronger,  and  the  char- 
acteristic differentiation  of  the  protoplasm,  consisting  in  the 
strongly  refractive  strand  in  the  axis  and  the  turbid  myelinlike 
outer  mass,  appears  at  the  point  of  stimulation.  From  here  a 
peculiar  alteration  spreads  gradually  further  over  the  pseudopod, 
in  that  first  upon  its  smooth  surface  a  few  myelinlike  droplets 
are  seen,  which  become  larger  and  with  the  development  of  the 
strand  in  the  axis,  dissolve  into  a  wrinkled  mass  on  the  surface. 
The  further  this  process  extends  from  the  point  of  stimulation, 
the  weaker  it  becomes  and  the  more  slowly  it  proceeds,  until  at 

1  Max    Verworn :    "Psycho-physiologische    Protistenstudien.      Experimentelle    Unter- 
suchungen."     Jena    1889. 


CONDUCTIVITY 


1-^3 


Fig.  15. 

Difflugia  urceolata.    A— Weak  local  stimulation  at  the  end  of  a  long  extended  pse 
B — Stronger  local  stimulation  applied  to  the  end  of  a  long  pseudopod. 


last  there  is  complete  disappearance.  (Figure  1."),  15.)  The 
pseudopod  has  at  the  same  time  retracted  to  a  c()nsi(leral)le 
degree.  If  a  still  stronger  stimulus  is  api)he(l  by  firm  |)rcssure 
at  the  end  of  the  pseudopod  the  ])rocess  takes  ])lace  witli  mucli 
greater  violence.  The  differentiation  of  the  ])rot()phism  spreads 
centripetally  from  the  point  of  stimulation  over  the  wliule 
pseudopod  with  great  rapidity,  and  produces  a  (juick  retraction 
in  the  same,  then  involves  the  op]>ositely  dirccte<l  j)scu(Ii)i)od, 
in  which  it  then  extends  more  and  more  slowly,  until,  proceeding 
in  a  centrifugal  direction,  it  is  at  last  gradually  comi)leteIy  oblit- 
erated. When  strong  stimulation  is  ai)i)licd.  the  i)rocess  occtirii 
with  such  rapidity  that  the  contraction  of  the  pseudopod  is 
almost    twdtchlike.      As    the    rapidity    of    the    conduction    alters 


124 


IRRITABILITY 


within  a  wide  limit  according  to  the  strength  of  the  stimulus 
and  the  distance  from  the  point  of  stimulation,  it  is  self-evident 
that  no  constant  figure  can  be  stated.  To  give  a  general  idea  of 
the  rapidity,  they  might  be  estimated  according  to  observations 
I  have  made  with  second  watch  and  ocular-micrometer  as  from 


Fig.  16. 

Diffiugia  urceolata.  A— In  non-stimulated  condition.  B— The  same  individual 
locally  stimulated  in  the  middle  of  a  long  extended  pseudopod.  The  excita- 
tion spreads  in  both  directions,  centripetal  as  well  as  centrifugal. 


within  a  slight  fraction  to  that  of  a  millimeter  in  the  second. 
When  a  very  long  extended  pseudopod  is  locally  stimulated  in 
the  middle,  the  response  spreads  from  the  point  affected  in  both 
directions  diminishing  in  intensity  and  rapidity.  The  excitation 
extends   equally   in   all   directions.      (Figure   16.)      These   facts 


CONDUCTIVITY 


125 


show  very  clearly  that  in  DiffluyUi  ilie  excitation  following  a 
localized  stimulus  is  dependent  on  the  intensity  of  the  stimu- 
lus, and  that  according  to  the  degree  of  this,  the  wave  pro- 
gresses in  either  stronger,  more  rai)i(l  and  extended,  or  weaker. 
slower   and   more   limited    manner.      With    the   greater   distance 


Fig.  17. 

Cyphoderia  margaritacea.     Result  of  localized  mechanical  stimulation  at  the  rnd 
of  a  long  extended  pseudopod.     A.  H.  C  -three  successive  staitcs. 


from  the  point  of  stimulation  the  excitation  undergoes  an  increas- 
ing decrement  of  its  intensity  and  rapidity  of  conduction.  Dif- 
ferent species  of  Diffliigia  which  I  have  investigated.  Diffluijia 
lohostoma,   nrceolata,   pyriformis,   have   shown   a   complete   con- 


126 


IRRITABILITY 


formity  in  this  respect.  A  great  number  of  other  fresh  water  and 
marine  rhizopods,  the  pseudopods  of  which  I  have  used  for  anal- 
ogous experiments,  although  differing  in  the  manner  of  reaction 
in  regard  to  the  extent  and  rapidity  of  the  course  of  excitation, 
manifest    exactly    the    same    fundamental    principles.      A    very 


Fig.  18. 

Cyphoderia  margaritacea.     Result  of  localized  mechanical 
stimulation  in  the  middle  of  a  long  extended  pseudopod. 


favorable  form  is,  for  instance,  the  much  smaller  Cyphoderiu 
margaritacea,  which  is  distinguished  by  a  somewhat  higher  degree 
of  excitability  and  rapidity  of  reaction.^  The  long  straightly 
extended  pseudopods  are  thinner  and  more  threadlike  than  those 

1  Max  Verworn :  "Die  Bewegung  der  lebendigen  Substanz.     Eine  vergleichend  physi- 
ologische  Untersuchung  der   Contractionserscheinungen."     Jena   1892. 


CONDUCTIX'ITV 


127 


of  Difflnyia  and  show  upon  stinuilalion  as  a  result  of  tlieir  local 
excitation  a  simple  contraction  into  cluini)s  of  the  .stimulated 
protoplasm  without  the  characteristic  differentiation  of  that  of 
Difflugia.      (Figure  17.)      In  the  case  of  the  marine  rhizoi>ods, 


J 


f 


Fig.  19. 

A  pseudopod  of  Orbitolites  complanatus  icf.  Fi«.  7'.  a  In  normal  condition. 
b — Severed  by  a  cross  section  near  the  end.  hf  Five  successive  stjycs 
of  the  effect,  b-d— The  pseudopod  retracts  by  centripetal  Huwinti  of  the 
protoplasm  contracted  in  the  shape  of  microscopic  balls  and  spindles.  «* 
and  f  The  pseudopod  begins  to  extend  again.  The  centripetal  flowintt 
balls  and  spindles  begin  to  disappear. 


Orbitolites  (Figure  19),  Amphistcgiua,  etc..  which  I  investij^ated 
at  the  Red  Sea,  the  conduction  of  excitation  takes  place  also  as 
in  Difflugia  with  a  decrement  of  intensity  and  rapidity  becoming 
larger  with  the  distance  from  the  point  of  stimulation  until  the 
wave  of  excitation  is  obliterated. 


128  IRRITABILITY 

A  sharp  contrast  to  this  type  is  formed  by  the  other  extreme 
as  represented  by  that  of  the  medullated  nerve.  As  an  indicator 
of  the  course  of  excitation  we  will  take  the  action  current  in 
an  isolated  nerve  of  the  frog.  If  this  is  stimulated  at  one  end, 
we  can  test  the  intensity  of  the  conducted  excitation  by  leading 
off  the  action  current  from  two  points  at  varying  distances  from 
the  one  influenced  by  the  stimulus.  Since  the  classical  discovery 
of  Du  Bois-Reymond  of  the  action  current  of  the  nerve,  we  know 
that  in  the  fresh  medullated  nerve,  if  observed  under  favorable 
experimental  conditions,  no  decrement  of  intensity  of  excitation 
during  its  course  from  the  point  of  stimulation  along  the  length 
of  the  nerve  can  be  demonstrated.^  If  unpolarizable  electrodes 
are  applied  to  a  nerve  in  such  a  position  that  they  are  equidistant 
from  the  cross  section  and  are  connected  with  apparatus  for 
testing  the  current,  it  will  be  found  that  there  exists  an  "unwirk- 
same  Ableitung"  in  the  sense  of  Du  Bois-Reymond,  that  is,  in 
which  there  is  no  demarcation  current.  When  a  tetanizing  cur- 
rent is  applied  to  one  end  of  the  nerve,  no  difference  of  potential 
between  the  two  nonpolarizable  electrodes  is  observed,  which 
indeed  would  be  the  case  if  excitation  with  its  current  of 
action  would  have  a  decrement  on  its  way  from  one  to  the  other 
point  of  leading  off  the  current.  This  fact,  which  has  been  repeat- 
edly confirmed,  shows  us  that  the  medullated  nerve,  under  normal 
conditions,  conducts  excitation  without  a  perceptible  decrement 
of  the  intensity. 

This  specific  property  of  a  medullated  nerve  is  in  conformity 
with  the  conditions  in  connection  with  the  rapidity  of  conduc- 
tivity. Since  Helmholtz-  has  devised  the  method  for  measuring 
the  rapidity  of  conduction  in  the  nerve,  this  investigator  himself 
and  numerous  others  have  studied  the  rate  in  different  nerves.* 
Helmholtz  found  the  rate  for  motor  nerves  of  the  frog  to  be 
27  meters  per  second,  for  the  sensory  nerves  of  man  60  meters, 

1  Du  Bois-Reymond:  "Untersuchungen  iiber  tierische  Electricitat."     II  Band.    1849. 

2  H.  Helmholtz:  "Messungen  iiber  den  zeitlichen  Verlauf  der  Zuckung  animalischer 
Muskeln  und  die  Fortpflanzungsgeschwindigkeit  der  Reizung  des  Nerven."  Miiller's 
Archiv.    1850. 

The  same:  "Messungen  iiber  die  Fortpflanzungsgeschwindigkeit  der  Reizung  in  den 
Nerven."     Zweite  Reihe,  Miiller's  Arch.   1852. 

3  Compare:  Hermann:  "Handbuch  der  Physiologie."     II,  1  Leipzig  1879. 


CONDUCTIVITY  129 

and  the  motor  nerves  of  man  34  meters.  Other  investigators 
have  obtained  quite  different  resuUs;  Hirsch,  for  the  sensory 
nerves  of  man,  34  meters;  Schclskc,  for  the  same,  •v^')-33  meters; 
De  Jaager,  26  meters;  v.  IVittich,  34-44  meters,  and  Kohlrausch. 
56-225  meters  ;  v.  IVittich  for  the  motor  nerves  of  man,  30  meters ; 
Piper^  finally  in  the  most  recent  investigations  about  ll'O  meters 
in  the  second. 

These  differences  may  be  explained  in  a  larijc  measure  by  the 
variety  of  the  methods  used,  in  part  also  ])y  liie  difference  in  the 
structures.  The  methods  employed  for  the  study  of  the  velocity 
have  also  been  used  to  solve  the  question,  whetlier  the  velocity  of 
the  excitation  wave  in  its  course  over  the  nerve  meets  with  a 
decrement  as  it  moves  further  and  further  away  from  the  jxiint 
of  stimulation.  Here  the  endeavor  w^as  made  to  study  the  differ- 
ence in  time  of  the  latent  period,  which  is  observed  by  the  indi- 
cator, when  the  nerve  is  stimulated  at  two  points  at  different  dis- 
tances from  the  muscle,  used  as  an  indicator,  or  from  the  wires 
leading  the  current  to  the  indicator.  The  more  recent  investiga- 
tors, as  Rene  Du  Bois-Reymoud,-  Engelmann,^  G.  Weiss.*  have 
arrived  at  the  same  conclusion,  that  the  rate  of  conductivity  in 
the  medullated  nerve  under  normal  conditions  is  the  same  at  all 
distances  from  the  point  of  stimulation.     (Figure  20.) 

The  medullated  nerve  shows,  therefore,  under  normal  condi- 
tions neither  a  decrement  of  its  conductivity,  nor  of  its  irritability. 
as  the  distance  of  the  w^ave  of  excitation  increases  from  that  of 
the  position  of  stimulation ;  this  means,  in  other  words,  that  excita- 
tion is  conducted  with  the  same  intensity  with  which  it  is  started, 
and  with  a  constant  rate  throughout  the  entire  course  of  the 
nerve. 

There  is,  nevertheless,  a  third  point  of  considerable  difference 

1  Piper:  "Ueber  die  Leitungsgeschwindigkcit  in  dcm  markhaltiRcn  mmschlichcn 
Nerven." 

The  same:  "Weitere  Mitteilungen  iiher  die  CieschwindiRkcit  dcr  Errrifiingalcitiing  «m 
markhaltigen  menschlichen   Nerven."     Pfliigers  .\rcb.   Hd.    1J7.  190'». 

2  R.  Du  Bois-Rcymond:  "Ueber  die  Geschwindigkcit  dcs  Nervcnprincip*."  Arch. 
f.   Anat.   u.    Physiol,    physiol.   Abt.    Suppl.    1900. 

3  Engelmauu:  "Graphische  Untersuchungcn  ubcr  die  Fortpflan/nnipmrichwindir 
keit  der  Nervcnerregung."     Arch.   f.   Anat.   u.    Physiol,   physiol.   .Abt.    1901. 

4  G.  Weiss:  "La  conductibilite  et  rexcitabilite  dcs  ncrf.s."  In  Journ.  dc  Phywol. 
et   de   Pathol,   generale    1903. 


130 


IRRITABILITY 


Fig.  20. 

Curves  of  muscle  contraction  obtained  by  stimulation  of  3  and  4  points  situated 
at  equal  distances  from  each  other  on  the  sciatic  nerve  of  the  frog.  The 
increase  of  length  of  the  nerve  stretch  corresponds  with  an  equal  increase  of 
the  latent  period  of  contraction.  From  this  follows,  that  the  rapidity  of  the 
wave  of  excitation  is  the  same  at  all  points  of  the  entire  length  of  the  nerve. 
(After  Engelmann.) 

between  the  types  of  conduction  of  excitation  in  the  rhizopods 
and  in  the  nerve.  Whereas  in  the  rhizopods  the  rapidity  of  con- 
duction is  dependent  upon  the  intensity  of  the  stimulus,  it  has 
been  long  known  as  the  result  of  investigation  by  Rosenthal, 
Briicke  and  Laiitenhach  and  at  a  more  recent  date  by  Gotch^  and 
Piper,-  that  in  the  nerve  of  the  frog,  as  well  as  in  man,  the  velocity 
is  not  dependent  upon  the  intensity  of  stimulation.  (Figure  21.) 
Contrary  results  have  been  obtained  by  a  few  early  observers 
wherein  the  latent  period  was  shorter  when  the  stimulation  was 
strong.     Nicolai^  explains  this  shortening  of  the  latent  period, 

1  Gotch :  "The  submaximal  electric  response  of  nerve  to  a  single  stimulus."  Journal 
of  Physiology,   Vol.   XXVIII,    1902. 

2  Piper :  Ueber  die  Leitungsgeschwindigkeit  in  den  markhaltigen  menschlichen 
Nerven.      Pfliigers  Arch.   Bd.    124,    1908,  und   Bd.    127,   1909. 

3  Nicolai:  "Ueber  Ungleichformigkeiten  in  der  Fortpflanzungsgeschwindigkeit  des 
Nervenprincips,  nach  Untersuchungen  am  marklosen  Riechnerven  des  Hechts."  Arch, 
f.   Physiologie   1905. 


CONDUCTIX'ITV 


131 


on> 

/ 

V 

O  V 

"^191 

926 

V 

- 

^ 

O/l 

X    -001     -002     003     OOi     005    006    OOr    OOS    009    010    on      0/2 

Fig.  21. 

Course  of  the  action  current  of  the  nerve.  The  thin  line  indicates  the  action  currcat 
produced  by  a  weak,  the  thick  line  the  action  current  produced  by  a  strong  stiaulu*. 
The  duration  of  the  action  current  is  the  same  in  both  cases.     (After  GotchJ 


resulting  from  the  application  of  strong  electrical  stimuli,  to  a 
spreading  out  of  the  "Stromschleifen"  from  the  i)oint  of  appli- 
cation and  consequently  there  is  a  shortening  of  the  stretch  of 
nerve  between  the  point  of  stimulation  and  tiie  indicator. 

This  conspicuous  difference  in  the  conduction  uf  tlie  two 
extreme  types  of  living  substance,  which  we  have  already  ob- 
served, arouses  the  question  as  to  what  properties  of  living  sub- 
stance bring  about  these  differences,  in  order  to  answer  this 
question,  it  is  necessary,  first  of  all,  to  make  some  general  .state- 
ments concerning  the  processes  of  conductivity. 

As  already  emphasized,  all  living  substance  possesses  the  cajva- 
bility  of  conducting  excitations  to  a  definite  degree.  W  e  may, 
therefore,  assume  that  the  same  fundamental  property  of  con- 
ductivity exists  in  all  substances.  A  fact  to  be  considered  in  tlie 
conduction  of  excitation,  is  that  the  i)rimary  breaking  down  of 
the  complex  molecules  at  the  position  of  stimulation  act  in  turn 
as  exciting  stimuli  ui)on  the  neighl)()ring  i)()rtion  of  the  living 
substance,  which  in  turn  undergoes  a  similar  decomposition.  And 
so  this  process  continues.  This  fact  is  evident  from  the  observa- 
tions on  the  process  of  excitation.     Ikil  the  nature  of  the  stimulus 


132  IRRITABILITY 

which  produces  the  breaking  down  of  the  complex  molecules 
upon  the  surrounding  molecules  is  a  problem  which  can  only  be 
studied  later.  Here  only  one  point  will  be  mentioned  in  advance 
concerning  the  intensity  of  the  stimulus.  It  is  apparent  from  the 
experiments  on  the  rhizopods,  that  the  greater  the  intensity  of  the 
stimulus  the  more  extensive  must  be  the  breaking  down  of  the 
living  substance.  A  stronger  primary  stimulation  must  also 
secondarily  produce  a  stronger  stimulus  in  the  neighborhood.  In 
other  words :  the  conduction  of  excitation  is  a  function  of  irrita- 
bility. The  greater  the  irritability,  that  is,  the  greater  the  number 
of  molecules  broken  down  in  a  unit  of  time  and  space  by  a  stim- 
ulus of  a  certain  intensity,  the  greater  also  is  the  conductivity  of 
the  living  system,  that  is,  the  stronger,  the  more  rapidly  and  the 
further  excitation  is  extended.  Conductivity  of  excitation  is, 
therefore,  unthinkable  without  irritability.  Both  are  inseparably 
connected.  The  conclusion  forced  upon  us  by  this  chain  of 
reasoning  admits  of  no  argument.  Nevertheless  the  endeavor 
has  been  made,  because  of  certain  evidence  at  hand,  to  show  that 
the  property  of  conductivity  could  exist  without  irritability.  A 
number  of  authors,  such  as  Schiff,^  Erb,^  Grilnhagen,^  Effron,^ 
Hirschberg^  and  G.  Weiss,^  have  observed  the  fact  that  in  spite  of 
a  more  or  less  strong  decrease  of  excitability  of  a  stretch  of  nerve, 
stimuli  applied  above  this  stretch  can  still  produce  a  conduction 
of  excitation  through  the  affected  part.  They  have  concluded 
from  this  that  it  is  possible  to  separate  the  conductivity  from 
irritability.  Erb  and  G.  Weiss  have  even  gone  so  far  as  to  directly 
express  the  opinion  that  capability  of  conduction  and  irritability 
involve  two  different  histological  elements.     In  contrast  to  this, 

1  Schiff :  "Uber  die  Verschiedenheit  der  Aufnahmsfahigkeit  und  Leitungsfahigkeit  in 
dem  peripherischen  Nervensystem."     Henle  u.  Pfliigers  Zeitschr.    1866. 

2  Erb:  "Zur  Pathologic  und  pathologischen  Anatomic  pcripherischer  Paralysen." 
Deutsches  Arch.  f.  Klin.  Med.   1869. 

3  Grunhagen:  "Vcrsuche  iibcr  intcrmitticrende  Ncrvcnrcizung."  Pfliigers  Archiv. 
Bd.  6,   1872. — Funke-Griinhagen."     Lehrbuch  der  Physiologic   Bd.  I,  1876. 

4  Effron:  "Bcitrage  zur  allgemeinen  Nervenphysiologie."  Pfliigers  Arch.  Bd.  36, 
1885. 

5  Hirschberg :  "In  welcher  Beziehung  stehen  Leitung  und  Erregung  der  Nervenfaser 
zu  einander?"     Pfliigers  Arch.  Bd.  39,  1886. 

6  G.  Weiss:  "La  condvictibilite  et  I'cxcitabilite  des  nerfs."  Journ.  de  physiol.  et  de 
pathol.  generale.  T.  V.  1903. — "Influence  des  variations  de  temperature  et  des  actions 
mechaniques  sur  I'excitabilite  et  la  conductibilite  des  nerfs."     Ibidem. 


CONDUCTIVn  \'  133 

other  investigators,  such  as  Hcrmanu}  Szpilmmm  aiui  I.uch- 
singcr,-  Gad,^  Piotroivski*  and  U'cdcuski/  have  more  or  less 
decidedly  taken  the  stand  that  an  actual  separation  of  irritability 
and  of  conductivity  does  not  exist.  Tlie  ai)i)arently  contradictory 
evidence  as  well  as  the  conflictini^  theoretical  views  have  Inren 
cleared  up  by  Wcrigo''  DeudrinosJ  NoW*  and  I-rohliclt.^  These 
investigators  have  shown  that  the  length  of  the  narcotized  stretch 
of  the  nerve  plays  an  important  nMe  in  the  obliteration  of  con- 
ductivity. It  has  been  found  by  the  ai)plication  of  a  stinnihis 
above  the  narcotized  stretch  of  nerve,  that  the  longer  this  stretch 
is,  the  less  is  the  reduction  of  irritability  which  ()l)literatcs  the 
excitation  wave  reaching  this  area.  I'urther:  The  shorter 
the  stretch,  the  greater  must  be  tlie  reduction  in  irrital)ility 
before  this  result  is  brought  about.  (Figure  22.)  In  other 
words,  the  conductivity  in  the  narcotized  nerve  is  dependent 
upon  the  length  and  the  irritability  of  the  narcotized  stretch. 
From  this  observation  the  important  fact  is  evolved,  that 
the  wave  of  excitation  meets  with  a  decrement  of  its  inten- 
sity in  the  narcotized  area.  This  decrement  becomes  larger  as 
the  wave  progresses  through  the  involved  stretch.  Further  it 
is  progressively  increased  as  the  amount  of  the  irritability  is 
reduced.     Finally,  wdien  the  stretch   is  long  enough,   the   wave 

1  Hermann:  "Handbuch   der   Physiologic."      Bd.   II.   I   Leipzig    1879. 

2  Scpilmann  titid  Luchsiuger :  "Zur  Bezichung  von  LcitunRSund  Errcff\ing»»cr- 
mogen  der  Nervenfaser."      Pfliigers  Arch.    Bd.   24,   1881. 

3  Gad:  "Ueber  Trennung  von  Reizbarkeit  und  Lcitungsfahigkcit  dcs  Ncrvcn." 
(Nach  Versuchen  des  Herrn  Sawyers)   Arch.   f.  Anat.  u.   Physiol,  physiol.  .\\A.   1888. 

Derselbe:  "Ueber  Leituiigsfahigkeit  und  Reizbarkeit  dcs  Ncrvcn  in  ihrcn  Hczich- 
ungen  zur  Langs  und  Querschnitts  erregbarkeit."  Nach  Versuchen  dcs  Ilcrrn  Piotrow- 
ski  Arch.   f.  Anat.  und  Physiol,  physiol.   Abt.   1889. 

4  Piotrozvski :  "Ueber  Trennung  von  Reizbarkeit  und  Lcitungsf.ihigkcit  dcs  Ncrvcn." 
Arch.  f.  Anat.  u.  Physiol,  physiol.  Abt.   1893. 

5  IVedenski:  "Die  fundamentalen  Eipenschaften  dcs  Ncrvcn  unter  Einwirkung 
einiger  Gifte."     Pfliigers  Arch.  Bd.  82.   1900. 

The  same:  "Excitation,  inhibition  et  narcosc."  Compt.  rcndus  du  v.  Confrw 
internal,  de  Physiologic  a  Turin    1901. 

6  Werigo:  "Zur  Fragc  iiber  die  Bcziehungcn  zwischcn  Errcpharkcit  nnd  I-citunf»- 
fahigkeit  des   Nerven."      (Nach   Versuchen   von   stud.    Rajmisf.    Pfliifrcrs   Arch.    Bd.    Tt.. 

1899. 

7  Deiidritws:  "Ueber  das  LeitungsvermoRen  des  motorischcn  FroMrhncrvcn." 
SNoH:  "Ueber  Erregbarkeit  und   Leitungsvcrmi>Kcn  dcs  motorischcn   Ncrtrcn  unlcr 

dem  Einfluss  von  Giften  und  Kfilte."     Zcitsch.   f.   Allgcm.   Physiol.   Rd.   III.   1007. 

9  Fr.  IV.  Frdhlich:  "Erregbarkeit  und  Leitfahigkcit  «!cs  Ncrvcn."  Zcitschr  f 
allgem.   Physiol.   Bd.   III.   1904. 


134 


IRRITABILITY 


of  excitation  is  obliterated.  This  important  fact  has  been  fur- 
ther estabHshed  by  the  experiments  of  Boruttau  and  FroJilich,^ 
in  which   they   studied   the   intensity   of   the   current   of   action, 


+f 


Fig.  22. 

Scheme  of  the  decrement  of  the  excitation  wave  in  the  narcotized  stretch  of  a 
nerve.  A— The  narcotized  stretch  (indicated  by  the  cross  section  of  the 
chamber)  is  30  mm.  long.  The  ordinates  of  the  dotted  lines  indicate  the 
amount  of  the  decrement.  If  the  decrement  is  slight  (upper  dotted  line),  the 
excitation  wave  passes  the  narcotized  stretch  and  increases  again  on  entering 
the  normal  stretch.  If  the  decrement  is  great  (lower  dotted  line),  the  excita- 
tion wave  is  obliterated  towards  the  end  of  the  narcotized  stretch  and  the 
muscle  remains  at  rest.  B— The  narcotized  stretch  is  15  mm.  long.  The 
decrement  is  slight.  The  excitation  wave  can  therefore  pziss  into  the  normal 
stretch  and  here  increase  again.  C— The  narcotized  stretch  is  15  mm.  long. 
The  decrement  is  great.  The  excitation  wave  is  obliterated,  therefore,  in  the 
narcotized  stretch,  and  the  muscle  remains  at  rest. 


produced  by  a  wave  of  excitation,  from  two  points  in  the  narco- 
tized stretch.    The  wave  of  negative  variation,  brought  about  by 

I  Boruttau  und  Frohlich:  "Erregbarkeit  und  Leitfahigkeit  des  Nerven."  Zeitschrift 
f.  allgem.  Physiologie  Bd.  IV,  1904.  The  same:  "Electropathologische  Untersuchungen 
ueber  die  Veranderungen  der  Erregungswelle  durch  Schadigung  des  Nerven."  Pfliigers 
Arch.    Bd.    105,    1904. 


CONDUCTIVITY  135 

the  excitation,  gradually  decreases  in  the  narcotized  stretch  as 
the  electrode  is  further  removed  from  the  point  of  entrance. 
Beside  a  decrement  of  iiitcusity,  as  the  investigations  of  Vrohlich^ 
prove,  the  wave  of  excitation  shows  a  decrement  of  the  velocity 
in  the  narcotized  stretch.  And  it  is  jjrohahle  that  the  wave  of 
excitation  extends  with  progressive  reduction  in  the  velocity, 
corresponding  to  the  decrement  of  intensity.  The  work  of  Koike* 
under  the  direction  of  Garten,  in  which  the  conclusion  arrived  at 
is  that  the  reduction  in  the  velocity  is  the  same  throughout  the 
narcotized  area,  should  not  be  accei)ted  as  conclusive  in  spite 
of  the  delicate  method  employed.  These  investigations  are  ex- 
tremely difficult,  being  in  the  field  of  the  most  delicate  of  present- 
day  methods.  The  decrement,  which  the  wave  of  excitation 
meets  with  in  its  progress  in  the  narcotized  stretch,  makes  the 
conflicting  testimony  concerning  the  apparent  separation  of  irri- 
tability and  conductivity  intelligible.  It  flepends  entirely  ui>on 
the  length  of  the  narcotized  area,  and  the  amount  of  reduction 
in  irritability  on  the  one  hand,  and  the  strength  of  the  stimuhis 
used  for  testing  the  irritability  on  the  other,  whether  the  con- 
ductivity will  disappear  before  the  irritability  or  vice  versa.  If 
I  test  the  irritability  in  the  narcotized  stretch  with  a  weak  stimu- 
lus, just  slightly  above  the  threshold,  then  by  slight  reduction  in 
the  irritability  complete  absence  of  response  occurs,  when  the 
same  stimulus  is  applied.  This  occurs  at  a  time  when  excitation 
reaches  the  narcotized  area  from  above  and  meets  with  a 
decrement  so  slight  that  it  can  pass  through  the  whole  narcotized 
stretch,  that  is,  when  the  narcotized  stretch  is  short  enough. 
If  I  test  the  irritability  of  the  narcotized  area  with  a  strong 
stimulus,  far  above  that  of  the  threshold,  irritability  will  he 
found  to  be  present  at  a  time  when  the  conductivity  for  the  exci- 
tation, coming  from  above,  is  already  obliterated.  Thi<  is  due 
to  the  fact  that  the  decrement  in  the  narcotized  area  is  already 
great  enough  to  bring  about  the  complete  disappearance  of  the 

iFrohlich:    "Die   Verringerung  di  r   Fortpflanziingsgcschwindigkcit  dcr   Ncnrrncrre- 
gung  durch  Narkose  und  Erstickung  des  Ncrvcn."     Zcitschrift  alljicm.  Phywologie  Bd. 

Ill,   1904. 

2Izuo    Koike:    "Uebcr    die     Fortlcitung    dcs    ErrcKuiiKSvorKaiiRS    -'     -i'lcr    narko* 

tisierten   Nervenstrecke."     Zeitsch.   f.   Biologic   Rd.   5.   1910. 


136  IRRITABILITY 

wave  of  excitation  coming  from  above.  This,  of  course,  only 
occurs  provided  the  length  of  the  narcotized  stretch  is  great 
enough.  The  separation  of  conductivity  and  irritability  is,  there- 
fore, only  an  apparent  one.  In  reality,  the  facts  obtained  from 
experimentation  indicate  that  with  the  reduction  of  irritability  the 
decrement  of  the  wave  of  excitation  increases,  whilst  the  shorter 
the  stretch,  the  smaller  is  the  decrement.  This  shows  that  con- 
ductivity is  a  manifestation  of  irritability. 

The  facts  just  mentioned  have,  however,  a  much  deeper  mean- 
ing. They  show  us  that  it  is  possible  by  means  of  narcosis  to 
convert  an  extreme  type  of  a  living  system,  with  decrementless 
conductivity,  into  another  extreme  type  of  living  substance,  in 
which  excitation  in  its  progress  meets  with  a  strong  decrement, 
like  that  seen  in  the  rhizopods.  The  same  results  may  also  be 
obtained  by  asphyxiation  and  other  forms  of  temporary  and  per- 
manent injury  of  the  nerve.  We  are,  therefore,  in  the  fortunate 
position  in  the  case  of  the  medullated  nerve  of  having  a  sub- 
stance to  study,  which,  depending  upon  conditions  which  are 
under  our  control,  may  become  a  type  in  which  conductivity 
occurs  with  or  without  the  presence  of  a  decrement.  We  can 
likewise  reduce  the  irritability  to  various  degrees,  producing  all 
intermediate  gradations  between  the  two  extremes.  This  latter 
is  particularly  valuable  in  that  it  permits  us  to  study  the  condi- 
tions in  one  and  the  same  substance  necessary  to  bring  about  the 
various  peculiarities  of  conductivity.  The  great  differences  in 
the  conductivity  of  excitation  are  conditioned  by  variations  in 
the  degree  of  irritability.  If  the  irritability  of  the  nerve  is  at  the 
normal  level  the  wave  of  excitation  progresses  to  the  end  of  the 
nerve  without  manifesting  a  decrement  of  its  intensity  or 
rapidity. 

If  the  level  of  irritability  of  the  intact  nerve  is  artificially 
reduced,  the  wave  of  excitation  meets  with  a  greater  decrement 
and  reduces  in  velocity,  and  in  fact  disappears  the  more  quickly 
in  the  stretch  of  nerve,  as  the  reduction  in  irritability  is  increased. 
These  three  factors,  irritability,  intensity  and  velocity  of  the 
progress  of  the  wave  of  excitation,  are  inseparable.  All  living 
substances  may  be  grouped  according  to  their  capability  of  con- 


CONDUCTIX  ITV  137 

ducting  excitation  into  a  long  scries,  starting  wiili  tliose  |Xisscss- 
ing  the  least  irritability,  as  we  found  in  the  rhizopuds.  then  tliosc 
having  greater  irritability,  as  the  smooth  muscle  and  ganglion 
cells,  then  those  with  still  greater  irritability,  as  the  strij>ed  muscle, 
and  finally  those  having  the  greatest  degree  of  irritability,  as  ihc 
medullated  nerves  of  the  warm-blooded  animal.  Should  the 
processes  of  excitation,  as  we  saw,  result  from  the  energy  pro- 
duction following  the  disintegration  of  the  labile  molecules  of 
the  living  substance,  then  the  degree  of  irritability  is  determined 
by  the  chemical  constitution  of  the  disintegrating  molecules,  i)y 
the  number  of  molecules  which  are  broken  down  in  a  defmitc 
space  and  a  given  time,  and  by  the  nature  of  the  disintegration 
itself.  All  of  these  individual  components,  if  we  observe  the 
problem  from  the  physical  standpoint,  are  manifested  by  the 
quantity  of  energy  production.  The  higher  the  irritability  of  a 
living  system,  the  greater  is  the  amount  of  energy  i)ro(luction  in 
a  given  time  and  space  which  the  stimulus  produces.  This  has 
particular  interest  from  the  standpoint  of  the  extreme  cases  of 
medullated  nerves  of  the  vertebrates  with  their  most  highly  devel- 
oped conductivity,  and  which  will  be  analyzed  in  somewhat  greater 
detail.  How  are  we  to  explain  their  decrementless  conductivity? 
When  we  study  the  decrement  of  the  excitation  wave  in  the 
series  of  living  substances,  before  alluded  to.  we  see  that  this 
reduces  with  a  progressive  increase  of  irritability.  Consequently 
the  extreme  irritability  of  the  nerve  is  a  manifestation  of  its 
decrementless  conductivity.  If  we  study  the  course  of  a  process 
of  excitation  and  its  conduction  in  its  molecular  details,  the  fact 
of  the  decrementless  conduction  indicates  that  in  excitation,  pro- 
duced by  a  stimulus,  the  same  number  of  specific  molecules 
capable  of  disintegration  are  broken  down  in  the  same  manner 
at  every  following  cross  section,  as  at  the  point  of  stimulation; 
or  in  other  w^ords :  an  equal  amount  of  energy  is  set  free  at  every 
cross  section,  which,  in  its  turn,  acts  as  stinuilus  t»^  the  next. 
etc.  Such  a  condition  presupposes,  however,  in  an  elementary 
fiber  of  the  nerve,  that  by  the  conduction  of  the  wave  of  excita- 
tion from  cross  section  to  cross  section,  all  tho-e  molecules 
capable  of  disintegration  are  broken  down.     If  it  is  assumed  that 


138  IRRITABILITY 

the  entire  number  of  molecules  capable  of  disintegration  do  not 
break  down,  but  only  a  certain  per  cent,  of  the  same,  then  it  would 
not  be  possible  to  conceive  of  a  molecular  structure  of  the  nerve 
in  which  this  would  take  place  without  decrement  of  the  wave  of 
excitation.  With  the  assumption  of  a  generally  homogeneous 
molecular  structure   (Figure  23,  a)   of  the  elementary  fibers  it 


0^  0^0  o 


^n°nO°0    °°0°°0   Ooo°°  0   0   0^0^,0        o^     o%%''o°oO 
y        O   00°    o\o  /O       O  0  0^  ^    ,        0^o°o°°0°0  0        0      °,  ^^O^^^O 

Fig.  23. 

would  be  entirely  incomprehensible  how,  with  the  decrementless 
extension  of  the  excitation,  individual  molecules  capable  of  break- 
ing down  could  escape  disintegration.  If,  on  the  contrary,  the 
molecular  structure  is  not  homogeneous  it  only  is  possible  to 
explain  a  conduction,  on  each  cross  section  of  which  an  equal 
per  cent,  of  irritable  molecules  break  down,  by  the  hypothesis 
that  the  irritable  molecules  are  in  their  turn  ordered  in  fiber- 
shaped  series  (Figure  23,  b)  within  the  elementary  fiber  and  are 
thus  protected  to  a  certain  degree  from  one  another  and  from 
transverse  conduction  of  excitation.  This  hypothesis  would, 
therefore,  only  mean  that  the  elementary  fiber  is   not  such  in 


CONDUCTIVITY  139 

reality  and  would  lluis  transfer  the  dithculty  to  the  uliiniaie 
fiber  unit,  for  which  a  liomo^cncous  molecular  structure  would 
have  to  be  presumed.  In  short,  whatever  may  be  the  assumption 
on  which  molecular  structure  of  elementary  fibers  is  based,  the 
fact  of  the  decrementless  conduction  peremptorily  demands,  from 
the  physical  standpoint,  that  from  cross  section  to  cross  section 
the  entire  number  of  irritable  molecules  are  broken  down.  This 
conclusion  is  highly  important,  for  it  indicates  very  clearly  that 
the  ''all  or  none  law"  is  applicable  to  the  nerve. 

This  gives  us  occasion  to  return  to  the  di.scussion  of  the  ques- 
tion, if  living  systems  really  exist  which  respond  in  accordance 
with  the  "all  or  none  law."  The  medullatcd  nerve  forms  an 
object  particularly  suited  to  serve  as  a  starting  point  for  the 
treatment  of  this  especially  important  i)roblem.  The  (juestion 
arises  in  this  connection,  if  the  validity  of  this  law  for  the  nerve 
can  be  tested  by  other  means. 

At  first  it  would  seem  as  if  the  application  of  the  "all  or  none 
law"  to  the  nerve  were  in  contradiction  to  the  well-known  fact 
that  a  weak  stimulation  of  the  nerve  produces  a  weak,  a  strong 
stimulation,  a  strong  response.  In  this  connection  Gotch^  has 
pointed  out,  as  the  result  of  experimental  studies  of  the  wave 
of  activity  of  the  nerve,  that  the  difference  in  response,  follow- 
ing the  application  of  stimuli  of  varying  strengths,  is  under- 
standable from  the  fact  that  threshold  stimuli  stimulate  only  a 
few  of  the  fibers  of  the  nerve  trunk,  wliereas  progressively  in- 
creasing the  intensity  of  the  current  involves  more  and  more 
fibers.  There  can  be  no  doubt  that  this  factor  explains  the  ditler- 
ence  in  the  strength  of  the  response.  Therefore,  in  reality  we 
do  not  find  here  a  contradiction  of  the  "all  or  none  law."  On 
the  other  hand,  the  fact  that  the  nerve,  in  contradistinction  to 
many  other  forms  of  living  substance,  the  ganglion  cell,  for 
example,  upon  a  weak  stimulation  does  not  show  the  phenomena 
of  summation,  even  when  the  stimuli  follow  each  other  in  a 
rapid  succession,  indicates  very  strongly  that  the  weakest  o|>cr- 
able  stimulus  produces  maximal  excitation,  so  that  tlie  response 

1  Gotch:  "The  submaximal  electrical  response  of  nerve  to  a  tingle  mmulu*." 
Journal  of  Physiology,  Vol.   XXVIII.    1902. 


140  IRRITABILITY 

cannot  be  further  increased.  But  above  all,  there  is  a  series  of 
facts,  which  have  been  gained  in  the  Gottingen  laboratory,  which 
demonstrate  apparently  without  doubt  the  validity  of  the  "all 
or  none  law"  for  the  medullated  nerve.  These  observations  I 
wish  now  to  consider  in  greater  detail. 

If  a  nerve  of  a  nerve  muscle  preparation  is  drawn  through  a 
specially  devised  glass  chamber  so  that  the  middle  portion  can 
be  narcotized  or  asphyxiated  and  the  nerve  so  arranged  that  it 
rests  upon  a  pair  of  electrodes  in  the  chamber  and  upon  a  second 
pair  without  the  chamber  and  centrally  located,  then  the  nerve 
can  be  narcotized  or  asphyxiated  and  thereby  the  alterations  in 
the  irritability  as  well  as  the  conductivity  can  be  followed.  In 
order  to  obtain  as  distinct  a  picture  of  this  alteration  as  possible, 
I  tested  continuously  the  threshold  of  stimulation,  which  just  pro- 
duced minimal  contraction  in  the  muscle,  and  Frohlich^  continued 
these  observations.  As  a  result  the  following  very  remark- 
able conditions  were  observed.  During  the  increase  of  the  depth 
of  narcosis  or  asphyxia  the  irritability  sinks  more  and  more  with 
regularity.  The  conductivity  remains  unaltered  for  a  long  time, 
as  the  strength  of  the  threshold  stimulus  is  not  changed  until 
irritability  has  fallen  to  a  definite  point.  When  this  is  reached, 
conductivity  disappears.  (Figure  24.)  The  most  important  point 
in  this  connection,  however,  is,  that  the  conductivity  disappears 
simultaneously  and  practically  momentarily  for  the  excitation 
produced  by  both  weak  and  strong  stimuli.  When  the  stimula- 
tion at  the  electrode  placed  centrally  to  the  chamber  does  not 
bring  about  response  for  threshold  stimuli,  maximal  stimuli  at 
the  same  time  also  become  inoperative.  This  is  a  very  interesting 
point,  the  importance  of  which  has  not  until  now  been  recognized. 
This  fact  is  not  in  harmony  with  the  view  held  until  now,  that  in 
the  nerve  fiber  different  strengths  of  stimuli  bring  about  excita- 
tion of  different  intensity,  and  are  then  conducted.  Let  us  now 
clearly  comprehend  this  problem. 

We  have  already  seen  that  the  wave  of  excitation  meets  with 
a   decrement   of    its   intensity   in   the   narcotized    stretch,   which 

1  Frohlich:  "Erregbarkeit  und  Leitfahigkeit  des  Nerven."     Zeitschr.  f.  allgem.  Physi- 
ologic, Bd.  Ill,  1904. 


COXDUCTIVITV 


Fig.  24. 

Curves  of  the  changes  in  irritability  (p)  and  conductivity    c    of  a  nerve  under  the  influence  of 

narcosis  or  asphyxiation.     (After  Fruhlkh.i 


increases  in  strength  as  the  irritabiHty  diniinislics.  It  the  value 
of  the  threshold  is  learned  by  stinuilatinj^  the  nerve  at  the  elec- 
trodes centrally  placed  to  the  chamber  with  minimal  siiimili.  it 
would  necessarily  follow  that  this  weak  stimulus  wcuild  lining 
about  a  corresponding  weak  excitation  of  the  individual  TiIkts 
and  the  wave  of  excitation  already  in  the  bej^inning  of  narcosis 
would  be  obliterated,  for  it  would  meet  with  a  decrement,  the 
result  of  the  reduction  in  the  irrital)ility.  A  wave  of  excita- 
tion of  minimal  strength  could  imdcr  these  conditions  no  longer 
reach  the  muscle,  even  in  the  beginning  of  narcosis.  In  spite 
of  this  the  excitation,  even  when  pro<iuced  with  ilireshold 
stimuli,  passes  through  for  a  long  time.  e\  en  when  the  irri- 
tability in  the  chamber  is  greatly  reduced,  as  sliown  by  testing 
with  the  electrodes  within  the  chamber.  This  is  not  consistent 
with  the  assumption  that  a  threshold  stinuilus  l)rings  alw-iut  tlu- 
minimal  excitation,  even  in  the  individual  nerve  fiber.  But 
further:  with  a  definite  decrease  of  irritabilitv  of  the  narcotized 


142  IRRITABILITY 

stretch  the  capability  of  conductivity  disappears,  and  indeed 
simultaneously  for  the  weakest. as  well  as  the  strongest  stimuli. 
If  it  is  assumed  that  weak  stimuli  bring  about  weak  excitations 
in  the  nerve  fiber,  it  must  most  certainly  be  expected  that  on  the 
cessation  of  the  response,  weak  stimuli  applied  at  the  central 
nerve  end  would  still,  by  slight  increase  of  the  intensity  of  stimu- 
lation, be  followed  anew  by  reaction  in  the  muscle.  This  is  all 
the  more  to  be  expected,  because  the  irritability  of  the  narcotized 
stretch,  as  shown  by  stimulation  with  the  electrodes  inside  the 
chamber,  very  gradually  decreases,  so  that  within  the  chamber 
stimuli  of  moderate  strength  are  still  effective.  Instead  the  capa- 
bility of  conduction  is  completely  obliterated,  and  even  the  strong- 
est stimuli,  applied  to  the  end  of  the  nerve,  produce  no  response 
in  the  muscle.  This  in  turn  does  not  agree  with  the  assumption 
that  the  intensity  of  excitation  varies  with  the  strength  of  the 
stimulus  in  the  individual  nerve  fiber.  The  facts  here  alluded  to 
are,  therefore,  either  not  correct,  or  the  intensity  of  excitation 
in  the  individual  nerve  fibers  is  independent  of  the  strength  of  the 
stimulus,  and  the  view  which  we  have  entertained  up  to  the 
present  in  this  respect  is  incorrect. 

In  order  to  examine  these  facts  once  more  on  an  extensive 
scale,  and  at  the  same  time  obtain  an  understanding  of  the  devel- 
opment of  the  decrement  in  the  narcotized  stretch,  I  have  re- 
quested Dr.  Lodhoh  to  register  as  many  accurate  curves  as  pos- 
sible in  which  the  positions  of  the  secondary  coil  of  an  inductorium 
are  the  ordinates  indicating  the  threshold  of  stimulation  at  four 
points  of  a  nerve  stretch.  Of  these  points  three  are  situated  at 
prescribed  distances  from  each  other  in  the  narcotized  or  asphyxi- 
ated stretch;  the  fourth  is  centrally  placed.     (Figure  24.)     As 


Fig.  24. 


CONDUCTIVITY  143 

might  be  expected  the  resuh  was  the  same  as  in  former  investiga- 
tions. They  show  however  even  more  strikingly  the  abruptness 
of  the  disappearance  of  conchicliviiy  simnhaneously  for  the  weak- 
est and  the  strongest  stimuli.  Tlie  curve  produced  by  the  centrally 
placed  electrode  remains  at  the  same  lieight  f(jr  a  considerable 
period,  then  suddenly  al)ruptly  declines.  Those  of  the  eleclro<lcs 
within  the  chamber  likewise  sink,  at  first  slowly,  then  with  in- 
creasing rapidity  in  successive  order  corresponding  to  the  dis- 
tance which  they  are  situated  from  the  point  of  exit  of  the 
nerve,  so  that  the  curve  of  the  most  distant  electrode  reaches  the 
abscissa  first,  that  of  the  electrode  nearest  the  muscle  in  the 
chamber,  last.  The  experiments  demonstrate  with  c<jmplete 
clearness  that  in  contrast  to  all  those  points  within  the  atlectcd 
stretch,  where  the  conductivity,  though  already  obliterated  for 
weaker  stimuli,  still  exists  for  stronger,  that  with  stimulaticjii 
of  a  point  towards  the  center  above  the  affected  stretch,  con- 
duction ceases  simultaneously  for  all  tlilYereni  .strengths  of 
stimuli.  This  last  state  at  the  points  within  the  affected  stretch 
might  be  ascribed  to  the  diminution  of  the  excitability  of  this 
stretch,  and  the  idea  entertained  that  the  weak  stimuli  no  longer 
produce  excitation  capable  of  further  conduction. 

This  assumption  is  contradicted,  however,  by  the  fact  that 
subsequently  to  the  disappearance  of  the  resi)onse  at  a  iK)int  sit- 
uated at  the  greatest  distance  from  the  place  of  exit,  an  eflect  of 
stimulation  can  be  obtained  at  the  nearest  point  to  the  exit  with 
the  same  or  even  less  strength  of  the  current.  As  the  irritability 
in  the  affected  stretch  is  reduced  at  all  j^oints  in  equal  measure, 
the  fact  of  a  weaker  stimulus  becoming  inoi)erativc  whilst  a 
stronger  remains  effective  can  only  be  attributed  to  the  circum- 
stance that  the  wave  of  excitation  set  free  at  some  point  of  the 
influenced  stretch  by  a  weaker  stimulus  is  sooner  obliterated  on 
its  way  to  the  muscle  than  that  produced  at  the  same  point  by  a 
stronger  stimulus.  These  experiments,  in  which  the  manifesta- 
tions of  the  nerves  in  response  to  stimuli  api)lied  centrally  al)ovc 
the  chamber  in  the  normal  stretch  are  compared  to  those  in 
response  to  a  stimulus  acting  on  the  affected  stretch,  dearly 
demonstrate  the  totallv  different  effect  in  both  cases.     In  stinuila- 


144  IRRITABILITY 

tion  of  the  centrally  situated  normal  stretch,  the  wave  of  excita- 
tion, which  enters  from  here  into  the  influenced  stretch,  is  oblit- 
erated at  the  same  point  simultaneously  for  the  weakest  as  well  as 
for  the  strongest  stimulus ;  stimulation  of  the  afifected  stretch,  the 
wave  of  excitation  which  is  set  free  at  one  point  by  a  weak  stimu- 
lus, is  obliterated  sooner  and  after  passing  through  a  shorter 
stretch  than  that  which  is  produced  by  a  stronger  stimulus.  It  is 
self-evident  that  in  the  first  instance,  in  which  the  stimulus  acts  on 
the  centrally  situated  normal  stretch,  the  wave  of  excitation, 
thereby  set  free,  must  in  passing  through  the  affected  stretch 
undergo  a  decrement  of  its  intensity.  If,  therefore,  the  wave 
of  excitation,  coming  from  above,  is  obliterated  exactly  at  the 
same  point,  whether  brought  about  by  weak  or  strong  stimuli,  the 
inevitable  conclusion  must  be  drawn  that,  whether  either  a  weak 
or  a  strong  stimulus  is  operative,  the  wave  of  excitation  must 
have  entered  into  the  influenced  stretch  from  the  normal  stretch 
with  exactly  the  same  intensity.  In  other  words :  the  weakest 
as  well  as  the  strongest  stimuli  produce  excitations  of  equal 
intensity  in  the  normal  nerve,  that  is,  the  ''all  or  none  law''  is 
valid  for  the  nerve. 

This  information  can  no  longer  be  doubted  in  the  presence  of 
such  evidence  as  was  presented  above.  This  indeed  is  a  fact  of 
far-reaching  importance  in  the  understanding  of  the  functional 
activity  of  our  nervous  system,  for  it  is  evident  that  the  differ- 
ence of  intensity  in  the  conduction  of  excitation  is  not,  as  has 
been  assumed  until  now,  the  result  of  the  conduction  of  vary- 
ing strengths  of  a  single  excitation  in  the  same  elementary 
fibers,  but  rather  the  involvement  of  a  various  number  of  fibers, 
and  that  a  series  of  processes  which  we  have  to  the  present 
attributed  to  the  varying  intensities  are  now  to  be  explained 
by  difference  in  the  duration  and  form  of  excitation.  This  gives 
us  an  entirely  different  but  nevertheless  a  more  definite  picture 
of  the  physiological  character  of  the  processes  in  the  nervous 
system.  Still,  this  question  belongs  to  another  chapter  of  phys- 
iology. Here  we  are  interested  in  the  fact  that  we  have  in 
the  nerve  a  form  of  living  substance,  in  which  irritability  has 
reached  a  high  degree,  and  every  stimulus  which  is  at  all  oper- 


CONDUCTIVITY  Ij:, 

ative  brings  about  disintegration  of  all  the  material  involved 
in  excitation,  and  consequently  the  i)roperty  of  conductivity 
in  the  nerve  reaches  the  state  of  highest  development  of  all 
living  structures,  in  that  the  medullated  nerve  conducts  with 
the  greatest  rapidity  on  the  one  hand,  and  on  the  other,  there  is 
no  decrement  of  the  velocity  and  intensity  of  excitation.  All 
these  characteristics:  the  existence  of  the  "all  or  none  law."  the 
rapidity  of  the  conduction  of  excitation,  the  absence  of  a  decre- 
ment in  the  velocity,  the  absence  of  a  decrement  of  the  intensity 
of  the  excitation  wave,  the  want  of  the  capability  of  summation 
of  excitation,  are  all  dependent  u\Hm  one  another,  f(jr  they  arc 
the  combined  expression  of  one  and  the  same  factor,  that  of  the 
high  state  of  irritability.  When  the  irritability  is  artificially  re- 
duced, then  the  nerve  approaches  more  and  more,  dej)ending  u\Hm 
the  amount  of  reduction,  to  the  series  of  living  substances  in 
which  we  found  the  protoplasm  of  the  rhizopoda  to  occupy  the 
other  extreme.  Between  the  normal  medullary  nerve  with  its 
maximal,  and  the  pseudopods  of  the  rhizoi)ods  with  their  minimal 
capability  of  reaction,  we  find  innumerable  gradations  in  groups 
of  living  substances.  \\  hethcr  or  not  other  forms  of  living  sub- 
stances follow  the  type  of  the  nerve,  whether  for  example  the 
*'all  or  none  law"  can  be  applied  to  the  skeletal  muscle  as  the 
investigations  of  KcitJi  Liicas^  seem  to  show,  rccjuires  further 
investigation. 

Finally,  there  arises  the  important  question  as  to  the  finer 
mechanism  of  conductivity.  The  progression  of  excitation  from 
cross  section  to  cross  section  in  a  living  system  is  brought  alx)ut 
by  the  decomposition  of  the  molecules  in  one  region  acting  as  a 
stimulus  and  producing  a  disintegration  of  the  molecules  in 
another  region,  etc.  \\'e  have  already  seen  that  the  intensity  is 
dependent  upon  the  amount  of  energy  produced  by  the  disinte- 
gration of  the  molecules  following  the  stimulus,  that  is.  u\K)n  the 
amount  liberated  in  a  definite  space  in  a  definite  time.  The  ques- 
tion which  now  arises  is  this:  What  form  of  energy  is  produced 

1  Keith  Lucas:  "On  the  gradation  of  activity  in  a  skeletal  muscle  f»l>cr."  Journal 
of  Physiology,  Vol.  IX,  1888.  The  same:  The  "all  or  none'*  contractiont  of  the 
amphibian  skeletal  muscIe-fiber.     Journ.  of  Physiology.  Vol.   XXXVIII.   1909. 


146  IRRITABILITY 

by  the  stimulus  at  the  point  of  stimulation,  which  acts  upon  the 
neighboring  molecules?  The  conduction  of  excitation  is  a  prop- 
erty of  all  living  substance,  and  we  may  presume  that  this 
occurs  in  all  living  systems  in  the  same  manner.  If  one  examines 
the  forms  of  energy  which  are  produced  in  a  living  substance  by 
the  breaking  down  of  the  molecules,  we  find  that  chiefly  three 
forms  of  energy  may  be  taken  in  consideration  in  the  problem 
of  conductivity :  heat,  electricity  and  osmotic  energy.  Light 
cannot  be  looked  upon  as  a  form  of  energy  which  is  produced 
by  all  living  substance,  and  the  other  forms  of  energy,  as  the 
chemical  energy  and  surface  tension,  remain  local.  At  a  first 
glance  one  is  inclined  to  assume  that  heat  is  the  form  of  energy 
which  is  liberated  by  the  breaking  down  of  the  stimulated  mole- 
cule and  which  spreads  to  the  neighboring  molecules  and  brings 
about  their  decomposition.  For  we  know  that  heat  facilitates 
dissociation,  and  the  analogy  between  living  substance  and  explo- 
sive material  is  very  close.  In  both  instances  the  decomposition, 
which  extends  over  a  great  mass  of  molecules,  is  accomplished  by 
the  heat  produced  in  the  breaking  down  of  a  few  molecules.  In 
fact,  the  conduction  of  excitation  of  a  nerve  can  in  many  respects 
be  compared  with  the  burning  of  a  fuse.^  Nevertheless,  it  must 
not  be  forgotten  that  this  analogy,  which  on  first  glance  seems  so 
apt,  upon  closer  observation  presents  serious  difficulties.  It  can 
be  experimentally  shown  that  an  increase  in  the  temperature  in 
the  living  substance  follows  stimulation,  but  it  is  also  known  that 
in  momentary  excitation  following  a  single  stimulus,  as  in  the 
muscle  after  the  application  of  an  induction  shock,  the  heat  pro- 
duction is  extremely  small.  This  difficulty  becomes  particularly 
apparent  if  we  endeavor  to  gain  an  approximate  idea  of  the 
numerical  proportions  of  the  irritable,  that  is  the  disintegrating 
molecules  to  the  remaining  mass  of  a  living  system.  The 
water  content  above  all  represents  an  enormous  proportion. 
If  we  calculate  this  to  be  for  the  nerve,  for  instance,  roughly 
about  75  per  cent.,  which  is  a  low  estimate,  only  25  per  cent. 

1  Compare  Pflilger:  "Ueber  die  physiologische  Verbrennung  in  den  lebendigen  Or- 
ganismen."  In  Pfliigers  Archiv.  Bd.  10,  1875.  Further:  L.  Hermann:  "Handbuch  der 
Physiologic,  Bd.  II,  Allgemeine  Nervenphysiologie,"   1879. 


CONDUCTIVITY  147 

of  dry  siil)stanccs  remain.  Even  (»f  this  25  per  cent,  by  far 
the  largest  part  is  apportioned  to  connective  tissue,  iur  which  15 
per  cent,  is  certainly  not  i(jo  hi^di  a  figure.  Neither  can  the  re- 
maining 10  per  cent,  of  dry  substances  be  regarded  as  consisting 
entirely  of  molecules  capable  of  decomi)osition.  For  in  this  is 
also  included  the  organic  reserve  material  of  the  axis  cylinder  pro- 
toplasm, which  is  doubtless  of  very  considerable  amount.  Furtiier. 
the  salts  and  products  of  disintegration,  for  which  the  estimate 
for  the  sum  total  would  i)rol)ably  not  be  too  low  if  we  assume  the 
amount  to  be  equal  to  that  of  the  group  si)ecially  concerned  in 
the  process  of  excitation.  As,  however,  a  constant  metabolism 
of  rest  takes  place,  these  last  molecules  or  atom  groups  arc  cer- 
tainly not  at  the  moment  of  entrance  of  the  stinudus  in  their 
entirety  in  a  condition  capable  of  decomposition.  It  is  (|uitc  cer- 
tain, therefore,  that  we  are  still  overestimating  the  amount  of  the 
molecules  capable  of  disintegration,  if  we  i)Ut  them  down  as  5  |)er 
cent,  of  the  entire  nerve  substance.  If  we  now  supi>ose  that  this 
5  per  cent,  of  irritable  molecules  are  broken  down  as  a  result  of 
stimulation,  95  per  cent,  of  nonirritable  substance,  separating 
these  irritable  molecules,  must  become  heated  to  such  a  degree 
by  the  disintegration  of  the  latter  that  the  amount  of  heat  suffices 
to  bring  about  decomposition  of  the  nearest  surrounding  mole- 
cules or  atom  groups,  for  otherwise  conduction  of  disintegration 
could  not  take  place  in  this  manner.  This  condition  presents  a 
serious  difficulty  for  the  assumption  that  heat  is  the  form  of 
energy  responsible  for  the  conduction  of  disintegration.  It  is 
true  that  we  cannot  reject  this  view  at  once  as  being  completely 
incorrect,  as  the  possibility  of  conduction  does  not  depend  uix)n 
the  absolute  amount  of  heat  which  reaches  the  next  molecule 
capable  of  decomposition,  but  upon  the  relative  amount  of  heat 
in  regard  to  the  degree  of  lability  of  the  irritable  molecules, 
of  which  we  cannot  even  approximately  make  an  estimate.  How- 
ever, by  a  comparison  with  other  highly  explosive  substances, 
such  as  iodide  of  nitrogen,  we  find  that  a  slight  trace  of  water 
applied  to  the  iodide  of  nitrogen  suffices  to  prevent  the  extension 
of  the  disintegration  process,  and  with  this  the  explosion  of  the 
whole  mass.     Nor  does  the  view  of  Pjh'njcr  remove  this  difticulty. 


148 


IRRITABILITY 


which  assumes  that  the  atom  groups  capable  of  breaking  down 
are  joined  together  by  a  chemical  linking  of  atoms  to  long  fiber- 
shaped  giant  molecules  through  the  whole  nerve  fiber,  for  this 
assumption  of  a  firm  structure  can  hardly  be  reconciled  with 
the  principles  concerned  of  metabolism. 

In  consideration  of  this  difficulty  it  seems  easier  to  assign 
the  role  of  mediator  of  disintegration  not  to  heat  but  to  elec- 
tricity. Production  of  electricity  is  likewise  a  property  of  all 
living  substance.  Differences  of  electrical  potential  between  two 
points  may  be  equalized  in  the  stretch  by  conduction  through 
the  intervening  space.  Electricity  would  then  fulfil  the  impor- 
tant conditions,  which  must  be  demanded  for  the  form  of  energy, 
acting  as  mediator  for  the  conduction  of  disintegration  from 
cross  section  to  cross  section. 


a  — {H 
A 


U 


3] b 


Fig.  25. 


Model  of  a  "Kemleiter."  A,  B— Glass  tube,  with  a  number  of  side  tubes 
filled  with  saline  solution,  through  which  a  wire  is  passed,  c  and  d— 
Side  tubes  with  electrodes  for  stimulation,  e  and  /—Tubes  for  con- 
nection with  a  galvanometer,    (After  Hermann.) 

Physiologists  even  at  an  early  date,  misled  by  the  apparent  like- 
ness in  the  conduction  of  excitation,  especially  in  the  nerve,  to 
that  of  electricity  in  a  metal  wire,  regarded  both  processes  as 
identical.  When,  however,  Helmholtz  first  demonstrated  experi- 
mentally the  rapidity  of  the  conduction  in  the  nerve,  the  thought 
that  electrical  conduction  was  concerned,  such  as  takes  place  in 
a  metal  wire,  had  to  be  abandoned,  as  the  velocity  shows  too 
great  a  difference  in  the  two  cases. 

The  observations,  on  the  other  hand,  on  the  conductivity  in  the 
so-called  "core  model,"  seemed  to  offer  another  possibility  of 
attributing  the  conduction  of  excitation  in  the  nerve  to  electric 


CONDUCTIVITY  149 

processes.  Mattcucci,  later  Ilcrnumn  and  finallv  Huruttau'  have 
endeavored  to  apply  the  results  obtained  when  electricity  is  intro- 
duced in  a  wire  covered  with  a  moist  envelope  (saline  solution), 
to  the  explanation  of  conductivity  in  tin-  nerve.  (  I'i^'ure  25  ) 
The  fact  has  been  shown,  that  in  sucli  a  model  the  ai)plicalion  of 
electricity  to  a  point,  as  a  result  of  polarization  between  the  moist 
envelope  and  the  metal,  produces  a  weak  local  current,  which  in 
turn  disturbs  the  electrical  potential  in  the  next  cross  section  and 
consequently  a  new  local  current  is  produced  and  so  on  through 
the  whole  length  of  the  wire.     (Figure  2i\.)     'Yh\<,  fact,  in  con- 


Fig.  26. 

Scheme  of  the  conduction  by  local  electric  currents 
in  a  "Kernleiter."    (After  Hermann.^ 

nection  with  the  apparent  similarity  in  the  differentiation  of  the 
axial  fibers  and  peripheral  envelope  in  the  nerve,  has  led  Borut- 
tau  to  apply  the  principles  of  conductivity  in  the  "core  model" 
to  that  of  the  nerve.  Then,  however,  A^cmst  and  Zcynrck  brought 
forward  their  theory,  according  to  which  the  galvanic  current  is 
operative  as  a  stimulus  in  that  it  brings  about  an  alteration  in 
the  concentration  of  the  ions  at  the  junction  of  two  ditTerent 
electrolites  which,  in  turn,  produce  local  currents.  Boruttau  then 
dropped  the  assumption  of  the  existence  of  a  simple  physical 
polarization  between  the  wire  and  the  envelope  and  replaced  it 
by  the  assumption  of  an  alteration  in  the  concentration  of  the 
ions  at  this  position.  Thereby  the  "core  model  explanation"  was 
already  altered  in  principle,  in  that  only  the  diflerentiation  of  a 
central  fibrilla  and  a  peripheral  enveloj)ing  substance  was  appro- 
priated.    It  seems  to  me  that  this  factor  can  likewise  be  consid- 

1  The  enormously  extensive  literature  nn  this  subject  up  to  the  mo»i  recent  date  it 
quoted  in  Cremer:  "Die  allgemeine  Physiologic  dcr  Nervcn."  In  Sagtls  Ilandbiirh  dcr 
Physiologic  des  Menschen,   Bd.   IV,   1909.      Braunschweig. 


150  IRRITABILITY 

ered  as  completely  dispensable  and  may,  therefore,  be  omitted; 
thus  nothing  remains  of  the  "core  model  explanation"  of  the 
conduction  of  excitation  in  the  nerve. 

The  results  of  continually  increasing  numbers  of  investigation 
in  recent  times  make  it  appear  almost  as  a  certainty  that  the  ele- 
mentary fibrillae  in  the  axis  cylinder  are  nothing  else  but  skeletal 
substances.  IVolff,^  Verworn^  and  others  have  first  expressed 
the  view  that  the  neurofibrillae  must  be  looked  upon  as  skeletal 
fibers  for  the  soft  neuroplasm,  and  more  recently  Lenhossek^  and 
especially  Goldschmidt^  have  confirmed  this  assumption  in  detail. 
Goldschmidt  has  shown  by  extensive  comparative  studies  of  cell 
mechanism  the  role  played  by  the  neurofibrillae  in  a  physical  con- 
nection as  internal  skeletal  formations,  and  has  proved  at  the 
same  time,  in  complete  unanimity  with  other  investigators,  their 
continuity  with  other  undoubted  skeletal  fibrillae.  By  this  the 
numerous  combinations  and  speculations  of  Apathy  and  Bethe 
concerning  the  part  taken  by  the  neurofibrillae  have  been  rendered 
untenable.  In  no  case  is  there  the  slightest  justification  to  regard 
the  apparent  ''Kernleiterstructur"  of  the  nerve  as  the  principal 
condition  for  the  process  of  conductivity,  for  should  we  dispense 
completely  with  this  point  for  the  theory  of  the  conduction  of 
the  nerve,  we  can  obtain,  solely  by  the  aid  of  the  facts  known 
today  in  physical  chemistry,  the  foundations  for  a  theory  of  the 
conductions  of  excitation  which  not  merely  renders  the  specific 
case  of  the  conduction  of  the  nerve  intelligible,  but  contains  at  the 
same  time  the  principles  of  the  process  of  the  conduction  of  exci- 
tation for  all  living  substance. 

On  the  basis  of  investigation  in  the  physical  chemistry  on  the 
properties  of  semi-permeable  membranes,  we  know  that  such 
membranes  produce  an  elective  effect  on  the  diffusion  of  dissolved 

1  M.  Wolff :  "Ueber  die  fibrillaren  Structuren  in  der  Leber  des  Frosches."  Anatom. 
Anzeiger  Bd.  26,  1905. 

2  Max  Verworn:  "Bemerkungen  zum  heutigen  Stand  der  Neuronlehre."  Medicin. 
Klinik,  Jahrg.   IV,   1908. 

3  M.  V.  Lenhossek:  "Ueber  die  physiologische  Bedeutung  der  Neurofibrillen." 
Anatom.  Anzeiger  Bd.  36,   1910. 

4  Richard  Goldschmidt :  "Das  Nervensystem  von  Ascaris  lumbricoides  und  megalo- 
cephala.  Ein  Versuch  in  den  Aufbau  eines  einfachen  Nervensystems  einzudringen." 
Ill  Teil.  Festschrift  zum  60  Geburtstage  Richard  Hertwigs  Bd.  II,   1910,  Jena. 


CONDUCTIVITY 


151 


substances.  This  is  in  the  way  thai  the  two  different  suhitiuns, 
separated  by  a  semi-permeable  surface,  do  not  follow  the  known 
laws  of  diffusion,  but  are  altered  in  thai  certain  substances  in 
contrast  to  their  rapidity  of  diffusion  i)ass  through  the  membrane 
or  are  prevented  from  entering  by  the  latter.  This  applies  like- 
wise to  the  two  kinds  of  ions,  which  arc  dissfx-iateti  in  diluted 
substances.  If  the  surface  exercises  a  selection  in  the  wav, 
for  instance,  that  the  positive  kations  are  allowed  to  pass  througli, 
whilst  the  negative  anions  are  held  back,  a  difference  of  iKjtential 
must  exist  between  the  two.  In  this  manner,  wherever  two  differ- 
ent solutions  are  separated  from  each  other  by  a  semi-permeable 
surface,  an  opportunity  occurs  for  the  taking  place  of  galvanic 
currents.  As  we  know,  living  protoplasm  by  reason  of  its  colloi- 
dal components  possesses,  in  common  with  all  colloidal  sub- 
stances, on  its  surface  the  properties  of  semi-permeable  mem- 
branes. Between  the  cell  and  the  medium,  therefore,  there  is 
ahvays  the  opportunity  for  the  occurrence  of  differences  of  elec- 
tric potential.    But  more.    We  likewise  know  that  protoplasm  itself 


R 
Fig.  27. 

Scheme  of  the  foam  structure  of  livintf  !wihstanc«.     A    In 
undifferentiated  protoplasm.     H     In  fibrilbc  protopUtm. 


■^■"T 


T-'-y" 


^^^Trn" 


^ssT'^:^ 


Protoplasm  of  different  cells,  showing  foam  structures.  A— Pseudopod  of  a  marine 
rhizopod.  The  protoplasm  only  shows  foam  structure  at  the  point  of  stimu- 
lation. B— Epidermic  cell  of  lumbricus.  C— Nerve  fiber.  D— Part  of  the  cell 
body  of  a  ganglia  cell.    (A-C  after  Biifschli,  D  after  Held.) 


CONDUCTIVITY  153 

represents  a  mixture  of  colloid  suhstances  and  actual  solutions. 
Frequently,  if  not  always,  living  structure  i)rcscnts  a  ni(>ri)hu- 
logical  differentiation  of  two  tyi)es,  when  seen  under  the  micro- 
scope, in  the  form  of  a  foam  structure  described  by  Biitschli. 
(Figures  27  and  28.)  If  we  suppose  that  with  the  disintegra- 
tion of  complex  molecules,  which  we  mu^t  assume  as  taking  place 
in  the  material  of  the  walls  of  ilic  i)r()toplasm  network,  sub- 
stances are  formed  which  are  subjected  to  electrolytic  dissociation, 
the  anions  and  kations  here])y  liberated  must  be  dilTused  from 
the  place  of  their  separation  into  the  surroundings.  Their  dif- 
fusion, how^ever,  is  restricted  by  the  pr()to|)lasmic  network.  The 
positive  ions  may  pass  through,  but  the  negative  ions  may  not. 
As  a  result:  the  reticulated  substance  is  the  seat  of  electric  dis- 
charge, wdiich  in  turn  gives  the  impact  to  the  breaking  down  of 
new  molecules  and  with  this  to  the  occurrence  of  new  j)otcntia! 
differences,  and  so  on,  consequently  the  disintegration  is  extended 
further  and  further  through  the  connected  masses  of  the  proto- 
plasmic framew^ork. 

This  theory,  founded  on  facts  gained  entirely  from  investiga- 
tion, would  involve  those  forms  of  energy  which  play  the  role  of 
activator  in  the  extension  of  the  breaking  down  of  the  molecule 
from  cross  section  to  cross  section,  namely,  the  osmotic  and  the 
electrical  energy.  Based  on  the  general  properties  of  physical 
chemistry  and  those  of  morphology  of  the  living  substances,  they 
W'Ould  be  applicable  to  all  vital  systems.  It  would  be  premature 
to  attempt  to  extend  this  assumjnion  and  further  develop  its 
specific  details,  above  all  to  make  it  responsible  for  the  si>ecific 
differences  in  the  i)rocess  of  the  conduction  of  excitation  in 
various  forms  of  living  substance.  For  this  our  knowledge  of 
the  properties  of  living  substance  is  still  far  too  incomplete. 
Nevertheless,  it  furnishes  us  even  now  with  various  points  of 
view^  for  the  further  analysis  of  a  series  of  vital  manifestation^, 
as,  for  instance,  the  facts  concerning  the  production  of  electricity, 
of  galvanotaxis,  chemotaxis  and  so  on.  This,  however,  exceeds 
the  limits  of  the  task  w^e  have  here  mapin-d  out.  We  are  con- 
cerned here  solely  with  the  general  principle  on  which  the  con- 
ductivity of  excitation  in  the  living  substrince  is  founded. 


CHAPTER   VII 

THE  REFRACTORY  PERIOD  AND  FATIGUE 

Contents:  Conception  of  specific  irritability.  Alteration  of  specific  irri- 
tability during  and  after  excitation.  Refractory  period  in  various 
forms  of  living  substance.  Absolute  and  relative  refractory  period. 
Curve  of  irritability  during  refractory  period.  Dependence  of  the 
duration  of  the  refractory  period  on  the  rapidity  of  the  course  of  the 
metabolic  processes  in  the  living  substance.  Dependence  on  tempera- 
ture. Dependence  on  supply  of  oxygen.  Theory  of  refractory  period. 
Refractory  period  as  basis  of  fatigue.  Fatigue  as  a  form  of  asphyxia- 
tion. Alterations  of  irritability  and  the  course  of  excitation  in  fatigue. 
Recovery  from  fatigue.  The  role  played  by  oxygen  in  recovery. 
Fatigue  as  an  expression  of  the  prolongation  of  the  refractory  period 
conditioned  by  the  relative  want  of  oxygen.    Fatigue  of  the  nerve. 

Every  living  system  possesses,  as  we  know,  a  peculiar  and  char- 
acteristic manner  of  reacting  to  stimulation.  The  muscle  responds 
with  a  contraction,  the  salivary  cell  with  production  of  saliva,  the 
luminous  cell  with  the  emission  of  light.  This  is  the  specific 
energy  in  the  sense  of  Johannes  Milller.  Every  living  system  is 
likewise  characterized  by  a  certain  degree  of  irritability,  which 
can  be  expressed  by  the  threshold  value  of  the  stimulus  at  which 
the  specific  reaction  is  just  perceptible.  This  degree  of  irrita- 
bility, by  which  the  system  concerned  is  distinguished,  may  be 
termed  its  specific  irritability. 

From  the  standpoint  of  the  conditional  method  of  investigation 
it  is  at  once  apparent  that  specific  energy,  as  well  as  specific  irri- 
tability, must  be  solely  determined  by  the  specific  conditions  exist- 
ing in  the  particular  system.  It  follows  from  this  that  every  alter- 
ation in  the  conditions  of  the  system,  that  is,  every  change  of  its 
state,  likewise  entails  a  corresponding  alteration  of  its  specific 
energy  and  its  specific  irritability.  It  is,  therefore,  self-evident 
that  the  alteration  of  the  state,  which  is  undergone  by  the  living 


THE  REFRACTORY  PERIOD  A\I)  FATKiL'E     155 

system  in  the  process  of  excitation,  l)rings  ahout  an  alteration  of 
its  specific  irritability.  Likewise  as  the  original  state  of  the  system 
is  restored  by  the  metabolic  self-regulation  after  the  course  of  an 
excitation,  the  specific  irritability  of  the  system  must  \)c  re- 
established. The  specific  irritability  is,  therefore,  a  proi>erty  of 
the  living  system,  which,  like  the  metabolic  eciuilibrium.  under- 
goes restitution  by  the  process  of  self -regulation  after  variation 
produced  by  a  stimulus  of  any  kind.  It  is  scarcelv  necessary  to 
repeat  each  time  that  this  is  only  ai)i)licable  within  the  physiologi- 
cal variations  and  for  a  limited  period,  during  which  the  altera- 
tions in  development  need  not  be  considered. 

These  alterations  of  the  specific  irritability  following  an  excita- 
tion and  their  compensation  through  the  metabolic  self-regulation 
will  now  claim  our  attention. 

That  the  specific  irritability  of  a  living  system  undergoes  a 
diminution  as  the  result  of  a  stimulus  of  long  duration  ha>  l>cen 
long  known  through  the  study  of  fatigue.  This  is  especially  so 
with  frequently  recurring  excitating  stimuli.  It  is  only  within  the 
last  decade,  however,  that  the  observation  has  been  made  in  a  few 
instances  that  a  single  momentary  excitation  is  likewise  followed 
by  such  a  reduction  of  the  specific  irritability.  lUit  that  this  is  a 
fact  of  general  physiological  fundamental  importance  for  the 
wdiole  field  of  response  to  stimulation  in  the  living  substance  has 
only  been  recognized  within  the  last  few  years. 

In  1876  Marey'^  found  that  the  irritability  of  the  heart  in  re- 
sponse to  artificial  stimulation  was  greatly  reduced  during  the 
systole,  and  that  recovery  took  place  during  the  following  dias- 
tole. (Figure  29.)  This  fact  was  already  apparent  from  the 
observations  made  by  Boivditclr  and  Kroticckcr.^  that  by  stimula- 
tion of  the  isolated  frog's  heart  with  single  induction  sluvks.  an 

1  Marcy:  "Des  excitations  artificielks  du  civiir.'*  Travaux  du  lah.  dc  .M.  Ma'ff 
II,  1875.  The  same:  "Des  mouvcmints  <|ui  produit  It-  ctrur  lors<iu'«l  «"»<  »oumi«  i  dc« 
excitations  artificielles."  Comptes  rcndues  dc  racadt-mic  des  micmcc*  T.  I-.  X.WII. 
1876. 

2  Bou'ditcli:  "Ueher  die  Kigentliiimlichkcitcn  dcr  Kcizbarkcit  wclchc  die  .Mi>»kcl- 
fasern  des  Ilerzens  Zeigen."     Arbeiten  aiis  drr  physioloRisclini  .Xnntalt  iii  I  cipxir.   1872. 

Z  Kroncckcr:  "Das  charakteristischc  Mcrkmal  «Icr  Hcr/miiskcH.cwcgijni:."  Hcitra^r 
zur  Anatomic  und  Physiologic  als  Festgabc  f.  Carl  I-udwig  zum  15,  Oct.  1874.  gvwid- 
met   von   seinen   Schiilcrn.      Leipzig   1874. 


156 


IRRITABILITY 


Fig.  29. 

Eight  series  of  heart  contractions.  The  dotted  lines  e  show  the  moment  of  an  artificial 
stimulus.  The  artificial  stimulus  is  ineffective  if  it  is  applied  before  the  height  of  a 
systole.  The  artificial  stimulus  becomes  the  more  effective  in  producing  an  extra 
systole,  followed  by  a  compensatory  pause,  the  later  it  is  applied  after  the  height  of 
the  systolic  contraction.    (After  Marey.) 


THE  REFRACTORY  PERIOD  AND  FATIGUE      15 


O  I 


artificial  systole  can  only  he  produced  with  certainty  wlien  the 
stimuli  succeed  each  other  at  certain  intervals,  which  must  l>c  the 
longer  as  the  strength  of  the  stimulation  is  weaker.  A/arry  calls 
this  period  of  reduced  irritability  "f^lutsc  rcfractairc"  of  the  lieart. 
The  refractory  period  of  the  heart  has  been  marie  the  subject  of 
a  great  number  of  investigations,  especially  by  liuf/clmautt  and 
his  pupils.  It  was  llngchnann^  especially  who  determined  more 
exactly  the  duration  of  the  course  of  the  refractory  period.  Mc 
found,  namely,  that  irritability  disap])ears  immediately  l>eforc 
each  systole  and  reappears  shortly  before  the  beginning  of  the 
diastole,  and  again  reaches  its  original  height  at  the  end  of  the 
diastole.  For  a  long  time,  however,  this  refractory  j>eriod  was 
looked  upon  as  a  special  peculiarity  of  the  heart.  It  was  not  until 
Broca  and  RicJiet,^  twenty  years  after  Marey's  in\estigations,  dis- 
covered an  analogous  refractory  period  for  the  motor  centers  of 
the  cerebral  cortex  of  the  dog.  Tliey  first  made  this  observation 
on  a  dog  affected  with  chorea,  in  which  tlie  choreic  movements 
rhythmically  occurred  in  intervals  of  one  second.  They  foun<l  that 
after  each  movement  electrical  stimulation  of  the  cortex  remained 
without  result  for  about  .5  seconds.  During  the  next  .25  seconds 
stimulation  was  followed  by  a  weak  response  and  it  was  not  until 
the  last  .25  seconds  before  the  next  movement  that  a  strong 
effect  was  produced.  They  also  found  in  the  normal  dog  a  re- 
fractory period  after  every  artificial  stimulation  equal  to  .1 
second,  so  that  the  number  of  contractions  brought  aUnit  by 
rhythmical  electrical  stimulation  w^ere  only  ten  per  second.  h'oUow- 
ing  this,  numerous  other  investigations  of  the  refractory  period 
have  been  made  on  the  central  nervous  system,  /wihirdrmakt'r^ 
and  Lans  have  observed  a  refractory  period  in  the  eyelid  reflex 
of  the  human  being  which,  on   stimulation  of  the  optic  nerve, 

1  Th.  IV.  Engclmann :  "Beobachtungcn  und  Vcrsuchc  am  «ii|»cndicrtcn  Ilcrxcti 
III.  Refractare  Phase  und  compcnsatorischc  Riihc  in  iJircr  Hrdrutung  (iir  den  I!cr«- 
rhythmus."     Pfliigers  Arch.    lUl.  59.   1895. 

2  Broca  ct  Riclict :  "Pt-riode  rcfractairc  dans  Ics  centres  nerveiix."  Comple»  rmdut 
de   I'academie   des    sciences    1897.      Further    Hichcl :   "l..i   vibration    nenreu«c."      RcTue 

scientific    Dec.    1899. 

3  Zzcaardemakcr  unci  Lans:  "Uebcr  das  Stadium  rclativer  fnerrrfUrVcil  aU 
Ursache  des  intcrmitticrcnden  Charakters  dcs  LidschlaKrcrtcxe*."  CenlralbUll  Ittf 
Physiol.   XIII,   1899. 


158  IRRITABILITY 

amounts  to  about  .5-1  second;  on  the  stimulation  of  the  trige- 
minus produced  by  blowing  on  the  cornea  on  the  other  hand, 
it  is  somewhat  shorter,  less  than  .25  seconds.  Zwaardemaker^ 
also  was  able  to  demonstrate  an  analogous  refractory  period  for 
the  swallowing  reflex  of  the  cat.  Further  a  refractory  period 
was  found  and  closely  analyzed  by  Verwornr  for  the  reflexes  in 
the  spinal  cord  of  the  strychninized  frog.  Dodge^  found  a  refrac- 
tory period  in  the  knee  jerk  reflex  of  man.  Gotch  and  Burch* 
showed,  by  two  induction  shocks  following  each  other  in  quick 
succession,  a  refractory  period  of  the  nerve,  which  is  char- 
acterized by  its  extremely  brief  duration.  They  found,  depending 
upon  the  temperature,  a  period  of  nonirritability  of  .001-. 008 
seconds  after  every  stimulus.  The  investigations  of  Miss 
Buchanan^  lead  us  to  conclude  that  there  is  a  refractory  period 
for  the  cross  striated  skeletal  muscle.  Miss  Buchanan  stimulated 
the  muscle  at  times  through  the  nerve,  at  other  times  directly 
after  elimination  of  the  nervous  element,  with  very  frequent 
electrical  stimuli  (about  1000  in  the  second)  and  found  by  means 
of  the  capillary  electrometer  a  rhythmical  reaction  of  the  muscle 
of  about  50-100  excitation  shocks  per  second.  Likewise  the 
Ritter  tetanus  produced  by  the  breaking  of  an  increasing  current 
proved  to  be  a  rhythmical  reaction  of  an  analogous  nature.  In 
a  more  direct  manner  Keith  Lucas^  has  determined  the  refractory 
stage  for  the  musculus  sartorius  of  the  frog.  He  allowed  two 
induction  shocks  to  act  successively  on  the  muscle  at  intervals 

1  Zwaardemaker :  "Sur  une  phase  refractaire  du  reflex  deglutition."  Arch,  inter- 
national de  physiologic  Vol.  I,   1900. 

2  Max  Verworn:  "Zur  Kenntniss  der  physiologischen  Wirkungen  des  Strychnins." 
Arch.  f.  Anat.  u.  Physiol,  physiol.  Abth.,  1900.  "Ermiidung  Erschopfung  und  Erholung 
der  nervosen  Centra  des  Riickenmarks."  Ibidem,  1900.  "Die  Biogenhypothese." 
Jena  1903.  "Die  Vorgange  in  den  Elementen  des  Nervensystems."  Zeitsch.  f.  allgem. 
Physiologie   Bd.   VI,    1907. 

Z  Dodge:  "A  systematic  exploration  of  a  normal  knee  jerk,  its  technique,  the  form 
of  the  muscle  contraction,  its  amplitude,  its  latent  time  and  its  theory."  Zeitsch.  f. 
allgem.    Physiol.   Bd.   XII,   1911. 

4  Gotch  and  Burch:  "The  electrical  response  of  nerve  to  two  stimuli."  Journ.  of 
Physiology,   Vol.   XXIV,    1899. 

5  Florence  Buchanan:  "The  electrical  response  of  muscle  in  different  kinds  of  per- 
sistent  contraction."     Journ.    of   Physiology,    Vol.    XXVII,    1901-1902. 

6  Keith  Lucas:  "On  the  refractory  period  of  muscle  and  nerve."  Journ.  of  Physiol- 
ogy, Vol.   XXXIX,   1909-1910. 


THE  REFRACTORY  PERIOD  AND  FATIGUE     159 

of  varied  duration  and  then  rcp;-istcrcd  the  action  currents  by 
means  of  the  capillary  electrometer.  lie  then  found  that  the 
second  stimulus  was  ineffective  for  about  .< )().')  seconds  after  tlic 
application  of  the  first  stimulus.  If  the  second  stimulus  follows 
somewhat  later,  it  produces  a  contraction  which  is  weaker  and 
has  a  longer  latent  period  the  nearer  the  second  stimulus  a|>- 
proaches  the  first  in  point  of  time.  (  iM^ure  'M).)  Massart^  anci 
Jennings-  likewise  observed  the  existence  of  a  refractory  i>erio<l 
for  the  myoids  of  unicellular  organisms  brought  about  liy  mechan- 
ical stimuli.  Massart  attributes  this  cessation  of  reaction  to 
stimuli  following  each  other  at  certain  intervals,  to  fatigue,  an 
explanation  which  has  been  disputed  by  J cunings  as  the  result  of 
his  investigations  made  on  Stentor  and  X'orticella.  Jennings  looks 
upon  the  behavior  of  the  infusoria  rather  as  an  "adaptation"  to 
the  stimulus.  Putter  was  the  first  to  see  in  this  the  existence  of 
a  refractory  period.  His  experiments  on  Spirostomun  ambigiuim 
in  1900  showed  a  refractory  period  in  the  reaction  to  rhythmical 
mechanical  stimuli.  I  wish  to  state,  however,  that  these  observa- 
tions of  Putter  have  not  as  yet  been  published.  Thus  the  exist- 
ence of  a  refractory  period  has  even  today  been  proved  for  a 
whole  series  of  very  different  kinds  of  substances. 

We  will  now  examine  the  alterations  of  irritability  which  are 
perceptible  during  the  refractory  period  to  comi)lete  restitution  of 
the  specific  irritability  of  the  particular  system,  and  endeavor  by 
the  analysis  of  their  special  conditions  to  render  them  comi)re- 
hensible  from  a  physical  standpoint  of  view. 

The  first  fact  to  take  into  consideration  is,  that,  as  is  shown  in 
the  heart,  the  refractory  period  begins  at  the  moment  of  the 
appearance  of  the  systolic  excitation.  The  irritability  of  the 
heart  is  absent  and  remains  so  until  the  excitation  has  readied 
its  highest  point,  that  is,  shortly  before  the  begiiming  of  the  dias- 
tole. From  this  point  the  restitution  of  irritability  begins,  which 
does  not  reach  the  maximum  until  the  end  of  the  diastole.  In 
other  words :  irritability  undergoes  the  greatest  reduction  by  dis- 

1  Massart:  Annales  de  I'lnstitut  Pasteur   1901. 

2  Jennings:  "Studies  on  reactions  to  stimuli  in  unicellular  org»niKnt."  IX. 
American  Journal  of  Physiology.   1902. 


t  I  I  I  ■  ■  I  I  '  I  ■  ■  ■  '  '  '  '  I  I  I  I  I  I  I  I  1  1 1  I  I  I  I  I  1 


5: '  I  !  I  I  ri  I  I  I  I  1  I  I  I  1  1  Ml  I  I  I  I  I  I  I  I  I  I  j  I  I  I  I 
SEC  'OJ  ^2  03 

A 


'    'I   I   I  I  I  I  I   I   I   I  I  I   I   I   I  I  1   I  I   1   I  I   I   I   I   I  I 


03- 


02- 


01- 


i 


SEC. 


I  M  I  ri  I  I  I  I  I  I'l  I  I  I  I  M  I  I  I  I 
01  OZ 


' ' ' ' '  1 1 1  1 1 1 1 1 1 1 1  ■  1 1 1 , 1 1 1 , 1 . ,  1 1 , , , , 


^J- 


I  '  I  I  I  I  I  I  [  I  I  I'l  I  I  r'l  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I  I 
SEC.  02  OZ  03 


'''''■'  I  I  ■''  I  ■  I  I  I  I  I  ■■  I  I  ■  I  I  1  I  I  I  1  I  » 


Fifl.  30. 

Curve  of  action  current  of  the  musculut  <uir1<>riu»  cxcitatrJ  by  two  mic- 
cessive  stimuli  iSt.  1  and  St.  2'.  The  effect  of  the  u-mnJ  fttimiihit 
is  the  less  and  the  latent  ix'rioJ  is  the  lontfer  the  more  giiKkly  the 
first  stimulus  is  followed  by  the  second.     'Keith  I. mas 


162  IRRITABILITY 

integration  produced  by  the  stimulus  and  is  restored  by  the  meta- 
boHc  self-regulation  following  the  decomposition. 

This  point  of  view  enables  us  to  interpret  this  state  from  a 
physical  standpoint.  In  this  discussion  on  the  relations  between 
irritability  and  the  extension  of  excitation,  I  have  taken  the 
amount  of  energy  which  is  produced  during  the  time  unit  and 
space  unit  in  a  living  system  as  the  general  standard  for  the 
degree  of  irritability,  at  the  same  time  duly  regarding  the  indi- 
vidual components  involved.  This  amount  of  energy  is  deter- 
mined in  a  given  system  by  the  quantity  of  substance  broken  down 
by  a  stimulus  of  a  given  intensity.  It  is,  therefore,  clear  that 
during  the  time  in  which  an  increased  disintegration  produced 
by  a  stimulus  takes  place,  the  irritability  in  response  to  a  second 
stimulus  must  be  reduced,  as  during  this  period  the  second  stimu- 
lus has  less  of  necessary  decomposable  substances  at  its  disposal, 
and  at  the  same  time  there  are  more  products  of  disintegration 
in  a  given  space.  If  a  living  organism  is  the  subject  of  consider- 
ation, to  which  the  "all  or  none  law"  is  applicable,  as,  for  instance, 
the  heart  at  the  moment  of  the  beginning  of  excitation,  irrita- 
bility is  completely  obliterated,  as  shown  by  the  fact  that  the 
second  stimulus  of  any  strength  remains  without  response,  for 
during  the  excitation  there  is  a  complete  breaking  down  of  all 
the  substances  capable  of  decomposition.  If,  on  the  contrary,  a 
system  is  the  subject  of  observation,  for  which  the  "all  or  none 
law"  is  not  valid,  then  irritability  is  merely  reduced  but  not  wholly 
obliterated  during  an  excitation,  and  whether  or  not  a  response 
is  obtained  to  the  stimulus  depends  upon  its  strength.  To  impress 
the  relations  between  the  degree  of  irritability  and  the  intensity 
of  the  stimulus,  I  have,  therefore,  employed  the  term  "relative 
refractory  period"  in  contrast  to  the  ''absolute  refractory  period," 
in  which  irritability  is  obliterated  even  for  the  strongest  stimuli. 
It  is  self-evident  that  irritability  must  again  increase  in  the  same 
degree  as  the  restitution  of  the  living  system  by  metabolic  self- 
regulation  takes  place,  for  the  more  molecules  capable  of  disin- 
tegrating are  restored  and  the  more  products  of  disintegration 
removed,  the  more  molecules  necessary  for  decomposition  in  the 
unit  of  space  are  attacked  and  broken  down  by  the  stimulus.    All 


TIIK  RKFRACTMRV  PFRIOD  AXD  FATUiUE     103 

these  are  self-evident  facts  wliicli  are  in  accordance  with  tlic  con- 
ception we  have  here  developed  of  tlie  course  of  the  process  of 
excitation  and  its  physical  nature.     Rut  anoiluT  iniiMjriant  {Kjini 
is  evolved  from  llic  ohservations  we  liave  made  of  the  nature  of 
the  process  of  self-regulation.      The  i)rocess  of  self-regulation  is 
founded  on  the  same  princii)le  as  that  which  governs  the  taking 
place  of  all  chemical   efjuilihriuni.   for  mctaholic  equilihrium   is 
merely  a  special  kind  of  a  chemical  ecjuilihrium.     The  <levelop- 
ment  of  a  chemical  equilihrium  hetween  reading  suhstances  and 
reaction  i)roducts  has,  as  known,  a  characteristic  course  in  regard 
to   its  duration.      If  the   rai)idity   willi   which   the  e(|uilil)riuni   is 
reached  is  expressed  hy  a  curve  in  which  the  ahscissa  represents 
the  time,  while  the  ordinates  signify  the  numl)er  of  contacts  of 
the  interacting  molecules,  the  rapidity  of  reaction  is  altered  with 
the  approach  to  the  equilil^rium   in   the   form   of   a  logarithmic 
curve;  that  is,  the  approach  to  the  state  of  e(|uilihrium.  wliich  is 
represented  hy  ordinate  value  zero,  takes  place  at  first  very  rap- 
idly, then  with  more  and  more  decreasing  speed,  for  with  llic 
decrease  of  the  number  of  reacting  molecules  an(i  the  increase 
of  the  amount  of  products  of  reaction,  the  contact  of  the  inter- 
acting molecules  and  w'ith  this  the  opi)ortuniiy  fur  the  reaction 
occurs   less   and   less    frequently.      Although   the   self -regulation 
of   metabolic   equilibrium    is   by   no   means   such   a   simple   pro- 
cess  as,   for  instance,  that   of   the   well-kncnvn   exam|)le  of  the 
forming  of  ethylester  from  acetic  acid  and  a-thyl  alcohol,  we  have 
still  in  every  case  to  deal  with  the  taking  place  of  a  chemical 
mass  equilibrium.     Hence  the  progress  to  the  metabolic  equilib- 
rium must  likewise  correspond  with  a  logarithmic  curve,  i.e..  resti- 
tution after  a  disturbance  of  the  e(|uilil)rium  must  take  place  at 
first  rapidly,  then  at  a  constantly  decreasing  rate.     For  reasons 
readily  to  be  understood  the  special  form  of  this  restitution  curve 
has  so  far  not  been  accurately  ascertained  for  any  kind  of  living 
substance.      Even    in   those   cases    where   the    restitution   occurs 
very  slowly  we  meet  with  the  diOiculty  that,  when  the  tests  are 
applied  which  are  necessary  to  determine  the  restitution  at  dif- 
ferent intervals,    with   each    testing   stimulus    irritability    is   each 
time  reduced.     Hence  the  construction  of  the  restitution  curve 


164  IRRITABILITY 

can  only  be  achieved  by  indirect  means,  and  we  must  content  our- 
selves with  the  ascertainment  of  a  smaller  number  of  its  points 
from  which  by  interpolation  its  form  can  be  constructed.    Indeed 
in  this  connection  a  certain  number  of  results  have  already  been 
gained  quite  sufficient  to  experimentally  confirm  the  correctness 
of  these  types  of  curves,  primarily  obtained  by  purely  theoretical 
deductions.    That  irritability  very  gradually  reaches  its  maximal 
height   has   been    already   shown,    as    previously   mentioned   by 
Bowditch^  in  his  investigations  on  the  influence  of  rhythmical 
induction  shocks  on  the  apex  of  the  heart  of  the  frog.    He  found 
that  in  order  to  produce  response,  the  weaker  the  stimuli  the 
longer  must  be  the  intervals  between  them.    It  follows  from  this, 
that  after  a  discharge  the  irritability  in  response  to  strong  stimuli 
reappears  more  rapidly  than  for  weak,  i.e.,  that  they  only  grad- 
ually regain  their  maximum.     The  exact  periods  of  time  for  the 
course  of  the  return  of  irritability  for  the  heart  have  unfortu- 
nately not  been  so  far  ascertained.    On  the  other  hand,  the  inves- 
tigations of  Ishikawa-  furnish  the  material  for  the  construction  of 
the  restitution  curve  for  the  centers  of  the  spinal  cord  of  the  frog. 
Ishikawa  did  not  employ  the  threshold  of  stimulation  as  an  indi- 
cator for  the  course  of  restitution,  but  used  instead  the  duration 
of  the  reflex  time  following  on  a  stimulus  of  a  certain  strength. 
The  reflex  time  is  greatly  prolonged  after  an  excitation  of  ex- 
tended duration  and  only  regains  its  normal  value  in  the  same 
degree  as  restitution  takes  place.     By  a  great  number  of  pains- 
taking  experiments   Ishikawa   ascertained   the    duration   of   the 
reflex  time  at  intervals  of  thirty  seconds  to  one  minute,  and  ob- 
tained  figures   which   show   that   restitution   does   actually   take 
place,    at    first    rapidly    and    then    with    constantly    decreasing 
speed.    The  detailed  study  of  the  course  of  self-regulation  of  the 
individual  forms  of  living  substance  will  doubtless  be  more  ex- 
actly  determined   in   the   near   future.      But   even   at   the   pres- 
ent we  are  fully  justified  in  describing  the  form  of  restitution 
curve  as  a  logarithmic  in  type.     Therefore,  a  relative  refractory 

1  Bowditch,  1.   c. 

2  Hidetsurumaru  Ishikawa:  "Ueber  die  scheinbare  Bahnung."     Zeitschrift  f.  allgem. 
Physiologic    Bd.    XI,    1910. 


THE  REFRACTORY  PERIOD  AXD  FATTGUR     163 

period  must  be  present  in  every  mclalxjlic  sclf-rcKu!atiuii  after 
an  excitation,  durinjj^  which  stron^a-r  stiiniih  produce  rcsjKjnsc, 
while  weaker  are  still  without  result.  This  is  a  fact  whidi,  as  wc 
shall  see  later,  is  of  fundamental  importance  for  the  compre- 
hension of  the  various  kinds  of  interference  resjxjnses  to  stimuli. 

From  the  information  here  p^ainecl  on  the  nature  and  origin 
of  the  refractory  period  the  conclusion  nuist  inevitably  Ik*  drawn 
that  in  all  living  substance  there  must  exist,  directly  following  an 
excitation,  a  period  of  time  in  which  its  irritability  is  reduced, 
that  is,  under  i)roper  conditions  a  refractory  i)eri(Ml  can  \)C 
demonstrated  for  every  living  (organism,  h'very  living  system 
possessing  irritability  undergoes  a  period  of  reduce<l  irritability 
at  the  time  of  and  subsequent  to  every  excitation,  for  cvcr>' 
excitation  momentarily  decreases  the  amount  of  products  capable 
of  disintegration  and  increases  the  disintegration  products  in  the 
unit  of  space.  As  restitution  involves  time,  a  stimulus  occurring 
in  the  phase  preceding  comi)lete  restitution  cannot  break  down 
the  same  quantity  of  molecules  as  would  l)e  the  case  after  the 
establishment  of  complete  restitution,  that  i>.  the  res|)onsc  is 
weaker,  the  irritability  is  decreased.  The  refractory  i>eriod  during 
and  subsequent  to  excitation  is  as  much  a  general  i)roi>erty  of  the 
living  substance  as  irritability  and  metabolic  self-regulation. 

This  conclusion  appears  so  self-evident  that  it  would  seem 
hardly  to  call  for  emphasis  were  it  not  that  even  at  the  present 
time  the  view  is  still  widely  held  that  the  refractory  jK-riod  is  a 
special  characteristic  of  certain  forms  of  living  substance.  This 
assumption  is  explained  on  the  one  hand  by  the  fact  that  our 
information  concerning  the  refractory  i)eriod  is  still  of  compara- 
tively recent  date  and  that  few  physiologists  are  in  the  habit  of 
connecting  special  observations  with  general  i)hysiological  con- 
ceptions, but  also  for  the  reason  that  some  investigators  have 
vainly  tried  to  find  a  refractory  i)erio(l  in  certain  forms  of  living 
substance.  Langcndorff  and  Wmtcrstcm.'  for  instance,  have  not 
succeeded  in  proving  a  refractory  period  for  the  si)inal  cord  of 
the    frog.      Langcndorff    stinudated    the    central    sciatic    stump 

1  Langcndorff  u.   JVintcrstcin  :  "IkitraRC  zur  Rcncxlchrc  "     IMn^rrr*.  Arrh.   Bd.   127. 

1909. 


166  IRRITABILITY 

with  two  stimuli  in  quick  succession  and  used  the  contractions 
of  the  triceps  as  indicator  of  the  response.  He  found  that  when 
the  stimuli,  if  consisting  in  either  single  induction  shocks  or 
faradic  shocks,  followed  each  other  even  at  intervals  of  .004 
seconds  the  second  stimulus  was  still  operative,  this  being  per- 
ceptible in  an  increase  of  the  contraction  or  with  greater  inter- 
vals of  time  in  a  summation  of  two  contractions.  Winterstein 
concludes  from  this  that  the  development  of  a  refractory  period 
after  a  stimulation  is  not  a  general  property  of  all  nerve  centers. 
If  the  experiments  of  Langendorff  failed  to  show  the  presence 
of  a  refractory  period  it  is  not  for  the  reason  that  this  does  not 
take  place  in  the  centers  of  the  spinal  cord  but  rather  results  from 
the  fact  that  the  conditions  for  the  investigation  were  not  suited 
for  its  demonstration.  In  fact,  Frohlich^  and  especially  Vessi^ 
have  incontestably  proved  the  existence  of  relative  refractory 
periods  in  the  normal  spinal  cord. 

If  the  existence  of  the  refractory  period  is  based  on  the  fact 
that  during  the  time  of  and  subsequent  to  an  excitation  the  quan- 
tity of  substances  necessary  for  disintegration  is  decreased  and 
that  of  the  breaking  down  products  increased,  and  if  it  is  limited 
by  the  restitution  of  the  substances  required  for  decomposition 
and  the  elimination  of  the  disintegration  products,  its  duration 
must  be  dependent  upon  the  length  of  these  processes.  All  fac- 
tors which  lessen  the  decomposition  and  hasten  the  metabolic 
self -regulation  must,  therefore,  shorten  its  duration.  This  is 
completely  confirmed  by  experimental  investigations.  As  can  be 
understood,  the  factors  of  special  interest  for  us  are  those  which 
influence  the  duration  of  the  refractory  period  in  the  physiologi- 
cal occurrences  of  the  organism. 

One  of  these  factors  is  temperature.  As  we  know,  the  rapidity 
of  chemical  reactions  increases  with  ascending  and  decreases  with 
falling  temperature.  As  in  the  disintegration  as  well  as  in  the 
restitution,  processes  are  chemical  in  nature,  it  is  to  be  expected 

1  Fr.  W.  Frohlich:  "Beitrage  zur  Analyse  der  Reflexfunction  des  Riickenmarks 
mit  besonderer  Beriicksichtigung  von  Tonus,  Bahnung  und  Hemmung."  Zeitschrift  f. 
allgem.    Physiologic   Bd.    IX,    1909. 

2  Julius  Veszi:  "Der  einfachste  Reflexbogen  im  Riickenmark."  Zeitschr.  f.  allgem. 
Physiologic  Bd.  XI,   1910. 


THE  REFRACTORY  PERIOD  ANT)  FATKiUE     167 

that  the  duration  of  the  refractory  jicriod  is  influenced  in  like 
manner  by  temperature.  Indeed,  Kroncckcr^  found  some  time  ago 
that  in  the  isolated  frog's  heart  a  much  more  fretjuent  rhythm  of 
stimulation  is  efTeclivc  at  a  hij^her  than  at  a  lower  temjKTaturc. 
When  the  heart  is  stimulated  at  a  lemi)erature  of  11-1'.*°  C.  with 
twelve  rhythmical  induction  shocks  in  the  second,  every  stinnilus 
is  operative  and  i)roduces  a  systole,  if  a  stimulus  of  the  same 
frequency  is  used  at  a  temperature  of  5°  C,  the  heart  resiK>nds 
merely  to  every  second  stimulus.  This  shows  that  the  refractory 
period  is  of  longer  duration  at  a  lower  than  at  a  higher  temi)cra- 
ture. 

A  factor  of  particular  interest  is  the  su])j)ly  of  oxygen,  for  we 
know  its  fundamental  imj^ortance  in  all  aerobic  organism'^  in  the 
breaking  down  of  the  living  substance.  The  life  of  these  organ- 
isms is  primarily  dependent  upon  the  supply  of  oxygen  from 
without.  Organic  reserve  substances  for  restitution  after  dis- 
integration are  contained  in  ample  quantity  in  the  reserve  stores  in 
the  living  cell  substance,  whereas  oxygen  is  present  in  very  small 
quantities  in  relation  to  the  former.  It  is,  therefore,  self-evident 
that  the  rapidity  of  the  breaking  down  processes  is  very  closely 
dependent  upon  the  amount  of  available  oxygen  at  hand.  Never- 
theless it  is  not  the  absolute  quantity  but  the  relative  amount  of 
oxygen  in  relation  to  the  momentary  reciuirement  which  is  of 
importance.  For  instance,  the  quantity  of  oxygen  present  may 
completely  suffice  for  the  oxydative  disintegration  in  tiie  metab- 
olism of  rest  or  at  lower  temperature,  whereas  the  same  amount 
would  be  much  too  small  to  meet  the  demand  increased  by  exci- 
tation or  at  higher  temperature.  In  the  latter  case  "a  relative 
deficiency  of  oxygen'  occurs.  I  have  introduced  the  term  "rela- 
tive deficiency  of  oxygen'"-  for  I  have  found  that  a  numlnrr 
of  authors  by  neglecting  the  relations  of  the  availal)le  oxygen 
to  that  which  is  required  at  the  moment  have  been  led  to  false 
conclusions.  There  is  no  living  object  so  preeminently  titled 
to   demonstrate   in   such   a    striking   maimer   the   de|K'ndence   of 

1  H.  Kroncckcr:  "Das  charakteristisclic  .Mcrkmal  dcr  Hcrximi^kclNrwce-.tns  " 
Beitrape  ziir  Anatomic  iind  Physiologic  als  KcstRabc  <'^'i  1  n-lwig  xum  1^  Oc!..l<r 
1874  gewidmet.   Leipzig   1874. 

2  Max  Verworn:  "Allgcmcinc  Physiologic."     V.  Auflagc.     Jma   1909. 


'^  4 


1 

k* 

g 

a 

•s* 

1 

c 

(4 

u 

# 

u 

X 

J£ 

u 

4-> 

4) 

^ 

O 

C 

(J 

Ul 

<fl 

o 

« 

X) 

E 

o 

lA 

X) 

It 

s 

m 

1 

^ 

J3 

b 

U 

u 

1 

^ 

• 

Q 

? 

c 
o 

ttO 

4-> 

. 

c 

3 

<u 

^ 

o 

2^ 

u 

c 

3 

C 

^M 

o 

.-i< 

(4 

t: 

a 

M 

a> 

<A 

1 

M 

"5 

o 

4-1 

(I) 

4-> 

c 

c 

o 

c 

(4 

o 

E 

T» 

o 

t/) 

i: 

j= 

44 

1 

4-1 

o 

> 

1 

1 

^M 

U 

CQ 

V. 

O 

J= 

h> 

u 

o 

c 

.c 

so    .2 

(4 

u 

B 

=  i 

M 

3 

4= 

c 

4-> 

c 

< 

E 

1 

X 

S 

o 

4-1 

^ 

"o 

^ 

u 

p 

Oi 

4-> 

c 

Si 

& 

e 

S 

in 

o 

^ 

, » 

4-1 

pH 

M 

<« 

c 

3 

4) 

2 

b 

J3 

^ 

S 

h 

4-1 

o 

^M 

U 

Si 

e^ 

<u 

u 

<j 

Xi 

c 

^ 

x> 

iq 

^ 

2 

■a 

c 

4-> 

X, 

rt 

oe 

.2 

^ 

c 

1 

4-> 

c 

s 

c 
o 

<u 

H 

tA 

E 

o 

X 

H) 

u 

ft 

oc 

u 

§^^* 


THE  REFRACTORY  PERIOD  AND  FATIGUE     1G'» 

the  duration  of  the  refractory  period  upon  the  supply  of  oxy- 
gen  as   the   spinal    cord   centers   of   the    frofj,    \yhen    ihcir    irri- 
tability   has    been    increased    to    the    inaxinuun    hy    strychnine.* 
Various  observers,  such  as  Lorcii,  Hucluitujn,  II.  z'ott  Hacyrr  and 
others,  investigated  the  action  current  by  the  cai)illary  electrom- 
eter.    As  a  means  of  studying  the  number  of  impulses  in  the 
strychnine  tetanus,  we  can  upon  the  basis  of  their  figures  roughly 
assume  the  number  of  imjmlses  to  equal  ten  per  second  at  rf>om 
temperature.    In  short,  in  the  freshly  strychninized  frog  the  dura- 
tion of  the  refractory  period  is  about  .1  second.     I'.y  means  of  the 
method  of  artificial  circulation  already  mentioned  a  deficiency  of 
oxygen  can  readily  be  brought  about.     It  ha-  been  demonstraleil 
that  the  rhythmic  in  contrast  to  the  contiiuKjus  method  of  intro- 
duction of  circulatory  fluid  is  superior  in  that  the  former  repro- 
duces more  closely  the  natural  conditions  of  the  circulation  of 
the  blood  and  renders  the  smallest  capillaries  more  |)enncablc. 
In  consequence  T  have  recently  constructed  a  small  appliance  for 
artificial    circulation,    which    accomi)lishes   this   in   a   manner   as 
simple  as  it  is  complete.  (  Figure  -U.)     The  fluid  flo\ys  from  a  ves- 
sel, E,  provided  with  an  outlet  tube  through  a  thin  rubber  tul>c 
into  a  glass  canula,  which  is  introduced  into  the  general  aorta  of 
the  frog,  F.    The  tube  is  automatically  occluded  by  the  rhythmical 
movement  of  the  armative  of  an  electromagnet.  I),  produced  by  a 
metronom,  B.    The  pressure  of  the  circulating  fluid  can  Ik  readily 
changed  at  will  by  varying  the  level  of  the  vessel  and  the  fre- 
quency of  the  pulse  by  the  rhythm  of  the  metronom.  which  makes 
and  breaks  the  current  to  the  electromagnet.-     In  this  way  it  is 
possible  to  artificially  replace  the  normal  circulation  with  satis- 
factory exactitude  and  substitute  for  the  blood,  circulating  in  the 
vessels  of  the  frog,  any  desired  fluid.     If  the  entire  cjuantity  of 
blood  of  a  frog  is  displaced  by  a  continuous  stream  of  oxygen- 
free  saline  solution   and   a   weak   strychnine   solution   is   injected 
with  a  Pravaz  syringe,  a  violent  strychnine  tetanus  api>o.irs  after 

1  Max  Verworn:  "Ermiidung  ErschopfuMR  iiiul  Erholung  dcr  ncrvo«cn  I  mir*  dc« 
Riickenmarks."  Arch.  f.  .\nat.  u.  Physiol,  physiol.  .M)t.  Suppl.  l">00.  Thr  Mine: 
ErmuduiiK  und  ErholuiiK.      Ik-rliiur   Klin.     Wochcnschrift    1901. 

2  As  I  have  not  yet  described  this  method  elsewhere  the  above  figure  will  ntfioe 
for  demonstration. 


IRRITABILITY 


B 


Fig.  32. 


Muscle  curve  of  strychnine  tetanus  in  a  frog  with  artificial  oxygen-free  circulation.  Lower  line  indicates 
seconds.  Upper  line  indicates  stimulation  by  induction  shocks.  A— A  single  shock  produces  a  long 
tetanic  contraction.  B— In  a  more  advanced  stage  each  shock  produces  a  tetanus  only  of  short 
duration.  C— In  a  still  more  advanced  stage  each  shock  brings  about  only  a  single  contraction  if  the 
stimuli  do  not  succeed  each  other  too  rapidly.  If  they  succeed  more  rapidly,  as,  for  instance,  in  a 
faradic  current,  only  the  first  shock  is  effective. 


the  lapse  of  a  few  seconds.  (Figure  32,  A.)  If  the  artificial  cir- 
culation with  oxygen-free  saline  solution  is  now  contained  in  the 
rhythm  of  the  natural  heart  beat,  the  further  reactions  can  then 
be  readily  observed.  The  first  long-continued  tetanic  attack, 
which  can  be  produced  by  a  slight  touch  of  the  skin,  is  followed 
by  a  whole  series  of  tetanic  convulsions  of  prolonged  duration, 
which  are  repeatedly  followed  by  periods  of  exhaustion.  I  wish 
to  emphasize  this  fact  once  more,  as  it  appears  to  me  as  not  with- 
out interest  for  the  understanding  of  the  question  of  reserve  sub- 


THE  REFRACTOKN'   IM-KloD  AM)   I-ATIGUE      1:1 

stances.    If  we  assume  tliat  at  the  moment  wlicn  tlic  entire  amount 
of  blood  is  removed  from  the  vascular  system,  no  oxygen  remains 
in  the  cells  of  the  spinal  cord  and  nuiscle,  then  disintepraiion  of 
the   living   substance   could    from   lliis   instant   take   |)lace  exclu- 
sively anoxydatively,   and   there  would  l)e  no   further  oxydativc 
breaking  down  into  carbon  dioxide  and  water.     The  energy  pro- 
duction   compared    in    ecjual    numljcr   of    molecules,    taking    the 
figures  of  Lesser  for  the  fermentation  of  sugar,  would  a|»proxi- 
mately  amount  to  about  ;3.8  jx^r  cent,  of  that  of  the  energy  pro- 
duction  in  the  oxydative  disintegration  of  dextrose  into  carUm 
dioxide  and  water.     In  reality,  however,  tlie  tetanic  convulsions 
are  at  first  exactly  as  violent  as  in  the  frog  with  a  normal  circu- 
lation.     There    simply    remains   the   assumptic^n.    therefore,    that 
either  the  disintegration  as  soon  as  it  becomes  a;ioxydative  in- 
volves relatively  greater  number  of  molecules  than  would  be  the 
case    if   it   were  oxydative    in    nature,    or  to    suj)pose    that    even 
after  the  complete  disi)lacement  of  the  bhxjd  a  certain,  though 
relatively  small,  amount  of  oxygen  is  present  in  the  cells  which 
for  a  short  time  suffices  for  the  taking  i)lacc  of  oxydative  disin- 
tegration and  wnth  this  an  almost  maximal  production  of  energy 
which  naturally  decreases  as  the  oxygen  is  consumed.     It  seems 
to  me  that  the  latter  supposition  contains  more  i)r()l)ability  than 
the  first.    To  return,  however,  from  this  observation  to  a  further 
consideration   of   the   animal   we   are   studying,   we   sec   how   tlic 
complete  tetanic  convulsions  in  the  refractory  period  which  we 
assumed  to  be  .1   second  are  gradually  transformed  into  incom- 
plete tetanus.    After  a  time  the  tetanic  convulsions  become  shorter 
after  each  stimulus  {  iMgure  32,  H  )  and  permit  us  to  distingmsh 
their  individual  movements,  even  though  the  latter  at  first  succect! 
each  other  still  very  rapidly.     Oradually  this  incomplete  tetanic 
convulsion  assumes  the  form  of  a  short  series  of  iiulividual  con- 
tractions, distinctlv  scj^arated  from  each  other  and  soon  a  stage  is 
reached  in  which  each  reaction  to  a  i)erii)hcral  stimulus  consists 
merelv  in  a  single  contraction.     (  iMgure  ;*>'i.  C.)     The  refractory 
period  is.  however,  even  now  less  than  a  second.     Nevertheless, 
with   a    further   continuation   of   the   experiment,   the   refractory 
period  becomes  more  and  more  prolonged,  so  that  stimuli  succeed- 


172  IRRITABILITY 

ing  each  other  at  intervals  of  less  than  a  second  are  without  effect. 
It  is  possible  at  this  stage,  as  Tiedemann^  did,  to  graphically  record 
the  reactions.  He  severed  the  sciatic  nerve  on  one  side  and 
stimulated  its  central  stump,  at  the  same  time  connecting  the 
triceps  w^ith  a  wanting  lever.  It  is  then  found  that  w^hen  the 
single  induction  shocks  follow  each  other  at  intervals  of  a  second 
or  more  every  stimulus  produces  a  contraction,  but  that  on  the 
contrary  only  the  first  stimulus  of  a  rhythmical  series  is  opera- 
tive and  all  those  succeeding  ineffectual,  if  the  stimuli  follow  each 
other  at  shorter  intervals.  The  refractory  period  becomes,  how- 
ever, more  and  more  prolonged.     The  rhythm  of  the  stimulus 


Fig.  33. 

Development  of  the  refractory  period  in  the  spinal  cord  of  a  strychninized  frog.  Lower 
line  indicates  seconds ;  upper  line  stimuli.  Of  a  series  of  stimuli  only  the  first  ones 
are  operative  with  decreasing  effect. 


must  become  continually  slower  if  each  individual  stimulus  is 
to  remain  effective.  If  the  rhythm  is  even  slightly  too  rapid 
only  the  first  few  stimuli  of  a  rhythmical  series  are  effective 
and  this  with  decreasing  response  and  later  no  contraction  at  all 
is  observed.  With  a  further  continuance  of  the  experiment,  the 
stimuli  are  only  effective  when  following  each  other  at  long 
intervals.  It  is  necessary  that  a  period  of  recovery  lasting 
several  seconds  must  take  place  before  the  following  stimulus 
can  meet  with  response.  (Figure  33.)  The  refractory  period 
can  gradually  be  prolonged  for  the  space  of  a  minute  or  longer, 

1  Tiedemann:  "Untersuchungen  iiber  das  absolute  Refractaerstadium  und  die 
Hemmungsvorgaenge  im  Riickenmark  des  Strychninfrosches."  Zeitschrift  f.  allgem. 
Physiologic   Bd.   X,   1910. 


THE  REFRACTORY  PERIOD  AXD  FATIGUE     173 

until  finally  irritability  does  not  reappear  at  all,  and  even  the 
strongest  stimuli  fail  to  produce  the  least  contraction.  The 
continuous  manner  in  which  the  refractory  perio<i  is,  in  the 
absence  of  oxygen,  more  and  ni(jre  prolonged  until  eventually  a 
prolonged  state  of  nonirritability  is  developed,  can  he  better 
followed  by  observing  the  experiment  than  when  dcscrilxrd  in 
words.  If  at  this  stage  instead  of  the  oxygen-free  saline  solution, 
defibered  blood  of  the  ox  shaken  in  air  or  a  saline  solution  satu- 
rated with  oxygen  is  circulated  in  tlie  frog,  restitution  is  often 
within  a  few  minutes  so  complete  that  tetanic  attacks  are  once 
more  produced  by  a  single  stimulus,  that  is,  the  refractory  perioti 
has  from  being  practically  nil  returned  to  the  normal.  This 
experiment  can  be  repeated  several  times  on  the  same  animal. 
It  is  invariably  found  that  the  refractory  period  is  prolonged 
by  the  withdrawal  of  oxygen  and  sh(jrtened  with  a  renewed 
supply. 

I  have  described  this  experiment  somewhat  in  detail  as  it  con- 
tains facts  which  are  the  key  for  the  comprehension  of  a  general 
physiological  process  of  paramount  imi)ortance.  I  refer  to 
fatigue.  The  refractory  period  and  fatigue  are  inseparably  con- 
nected, for  fatigue  is  founded  on  the  existence  of  the  refractory 
period  and  is  an  expression  of  prolongation  of  the  former,  brought 
about  by  want  of  oxygen.  This  is  shown  at  once  by  closer 
analysis.  It  is  here  necessary  to  ditTerentiate  somewhat  more  in 
detail  the  factors  wiiich  bring  about  the  prolongation  of  the 
refractory  period  in  deficiency  of  oxygen. 

If  we  first  turn  our  attention  to  the  normal  refracitjry  j>eriod 
wdiich  occurs  in  a  system  in  metabolic  equilibrium  of  rest  in 
direct  connection  with  dissimilatory  excitation,  following  a 
momentary  stimulus,  we  find  that  reduction  of  irritability  or, 
more  exactly  expressed,  the  lessening  of  the  resj)onse  is.  as  wc 
have  seen,  determined  by  the  time  involved  in  the  metalK)lic 
decomposition  and  recovery.  P)Oth  these  i)rocesses  recjuire  time 
and  until  their  completion  the  quantity  of  substance  demanded 
for  the  oxydative  disintegration  is  decreased  in  a  given  space. 
and  every  stimulus  nui.st  conseciuently  be  followed  by  a  weaker 
response.     Our  conceptions  of  the  physical  details  of  these  pro- 


174  IRRITABILITY 

cesses  depend  essentially  upon  the  question,  if  the  oxydative  dis- 
integration itself  in  the  given  living  system  occurs  in  one  single 
phase,  in  that  the  oxygen  is  the  activator  for  the  oxydative  split- 
ting up  of  the  carbon  chain,  or  if  this  takes  place  in  two  periods, 
in  which  the  carbon  chain  is  first  anoxydatively  split  up  into 
larger  fragments  by  the  stimulus,  which  are  then  seized  upon  by 
the  oxygen  to  be  split  up  into  carbon  dioxide  and  water.  As  we 
have  seen,  this  question  must  remain  for  the  present  undecided 
as  far  as  the  metabolism  of  rest  as  well  as  the  excitation  pro- 
duced by  a  single  momentary  stimulus  is  concerned.  It  is  highly 
probable  that  a  uniformity  of  the  process  for  all  living  systems 
does  not  exist.  We  are,  therefore,  not  justified  in  assuming  that 
these  special  chemical  processes  resulting  from  single  stimuli  are 
uniform  throughout  the  refractory  period. 

On  the  contrary  it  is  different  in  the  case  of  oxygen  deficiency. 
Here  we  see  with  increasing  want  of  oxygen  a  constantly  increas- 
ing duration  of  the  refractory  period,  a  prolongation  which  may 
be  attributed  to  the  retardation  of  the  oxydative  disintegration. 
It  is  necessary,  however,  that  we  now  study  more  clearly  these 
alterations  brought  about  by  the  deficiency  of  oxygen. 

If  we  follow  the  course  of  the  changes  from  that  of  the  normal 
state  of  equilibrium  of  metabolism,  wherein  oxygen  is  sufficient 
to  bring  about  complete  disintegration  of  the  molecules  to  the 
formation  of  carbon  dioxide  and  water,  we  must  assume  in  spite 
of  the  great  explosive  rapidity  of  this  process  on  the  basis  of  our 
chemical  knowledge,  that  first  a  series  of  intermediate  products 
are  produced  before  finally  the  end  products  are  formed.  In 
this  way  the  oxydative  disintegration  produced  by  a  stimulus 
becomes  more  and  more  prolonged  by  an  increasing  want  of 
oxygen.  If,  as  I  have  previously  suggested,  the  amount  of  energy 
which  is  liberated  in  a  given  space  and  time  by  an  excitating  stimu- 
lus is  taken  as  a  standard  of  irritability,  it  is  apparent  that  the 
more  the  oxydative  disintegration  following  a  stimulus  is  retarded, 
the  greater  must  be  the  decrease  in  irritability.  The  less  oxygen 
there  is  at  disposal  and  the  more  incomplete  the  oxydative  break- 
ing down,  the  smaller  is  the  degree  of  irritability,  the  weaker  the 
response  and  the  slower  the  return  of  irritability  after  every 


THE  REFRACTORY  PERIOD  AND  FATIGUE     175 

stimulus.  In  other  words,  witli  the  increasing  deficiency  of 
oxygen,  the  response  is  not  merely  reduced  for  every  slimulus, 
but  the  duration  of  the  refractory  period  is  likewise  progressively 
prolonged  until  finally  with  an  ahsolute  want  of  oxygen,  constant 
and  complete  depression  takes  i)lace.  In  the  genesis  of  this  pro- 
cess another  factor,  however,  has  the  same  effect. 

While  with  a  sufticient  supply  of  oxygen  disintegration  leads 
to  the  formation  of  carbon  dioxide  and  water,  therefore  to  end 
products,  v^hich  can  quickly  and  easily  be  removed  by  diflusion, 
the  want  of  oxygen  produces  complex  products  of  incomplete 
combustion  and  finally  of  anoxydative  deconijwsition,  such  as 
lactic  acid,  fatty  acids  and  even  more  complex  substances  in  con- 
stantly increasing  quantities.  These  products  permeate  the  protf>- 
plasmic  surfaces  with  great  difficulty,  if  at  all.  and  as  they  cannot 
subsequently  be  oxydatively  split  up,  constantly  accunuilate. 
These  asphyxiation  substances,  as  they  may  be  briefly  termed, 
produce  a  depressing  effect  on  further  disintegration.  This  can 
be  experimentally  demonstrated. 

For  this  purpose  I  have  modified  the  experiment  previously 
described  in  the  way  that  after  every  introduction  into  the  blood 
of  oxygen-free  saline  solution  and  after  the  injection  of  strych- 
nine, the  artificial  circulation  was  stopped  so  that  stagnation  of 
the  oxygen-free  saline  solution  took  place  in  the  vascular  system. 
The  processes  then  occurred  in  exactly  the  same  manner  with 
the  exception  that  the  state  of  non-irritability  appeared  somewhat 
earlier.  If  after  the  beginning  of  complete  depression  artificial 
circulation  with  oxygen-free  saline  solution  w^as  again  started,  a 
certain  degree  of  recovery  took  place  within  one  or  more  minutes. 
The  stimuli  were  once  more  effective  and  i)roduccd  a  numl>er 
of  contractions.  At  times,  several  single  contractions  following 
each  other  in  more  or  less  quick  succession,  could  be  brought 
about.  But  complete  recovery  or  the  appearance  of  even  incom- 
plete tetanic  convulsions  was  never  again  obtained,  whereas  by 
the  introduction  of  oxygen  comi)lete  recovery  could  at  once  l)C 
brought  about.  If,  however,  the  circulation  with  oxygcn-frcc 
saline  solution  w^as  continued,  irritability  gradually  decreased. 
The  refractory  periods  after  the  individual  stimuli  became  longer, 


176  IRRITABILITY 

and  in  spite  of  continuous  artificial  circulation  irritability  again 
disappeared.     The  experiment  shows  that  by  the  circulation  of 
oxygen-free  solution  irritability  can  simply  be  reduced  up  to  a 
certain  degree.     This  partial  restitution  is  produced  by  washing 
out  the  depressing  metabolic  products.     Being  desirous  to  verify 
the  results  of  this  investigation  with  greater  exactitude  I  have 
requested  Dr.  Lipschiits^  to  repeat  the  experiments,  taking  the 
utmost  possible  precaution  in  respect  to  the  absolute  exclusion  of 
oxygen.     Lipschiitz  has  tested  the  normal  saline  solution  made 
oxygen  free  with  the  sensitive   Winkler  method,  in  which  the 
slightest  trace  of  oxygen  is  shown  by  the  oxydation  of  manganous 
chloride  to  manganic  chloride  in  which  the  latter  in  a  saline  solu- 
tion sets  free  an  amount  of  iodide  from  iodide  of  potassium  corre- 
sponding to  that  of  the  consumed  oxygen.     These  experiments 
of  Lipschiitz  have  shown  that  even  with  the  absolute  exclusion 
of  the  slightest  trace  of  oxygen  a  partial  recovery  can  be  brought 
about  by  artificial  circulation.    There  can  be,  therefore,  no  doubt 
that  recovery  is  actually  founded  on  the  removal  of  the  depress- 
ing asphyxiation  substances  by  artificial  circulation.     Moreover 
Fillip  has  previously  succeeded  in  the  laboratory  at  Gottingen  in 
obtaining  by  the  same  methods  a  corresponding  result  for  the 
nerve.     In   both   cases   the   experiments   are   extremely   compli- 
cated and  must  be  carried  out  with  the  most  painstaking  care. 
The  depressing  influence  of  the  asphyxiation  products  need  not 
be  regarded  as  a  specific  effect  of  poisoning.    It  can  be  solely  an 
expression  of  mass  relations,  if  we  assume  that  the  anoxydative 
decomposition  is  controlled  by  a  chemical  equilibrium  between 
masses  capable  of  disintegrating  and  products  of  the  disintegra- 
tion.   It  is  not  possible  to  give  any  detailed  account  as  to  the  part 
taken  by  accumulating  asphyxiation  substances  in  the  prolonga- 
tion of  the  refractory  period.     Indeed,  we  must  for  the  present 
relinquish  the  attempt  to  delimitate  quantitatively  the  part  taken 
by  the  individual  constituent  processes  in  the  symptoms  of  de- 
pression resulting  from  the  deficiency  of  oxygen.    We  can  merely 

1  Alexander    Lipschiita:    "Ermiidung    vmd    Erholung    des    Riickenmarks."      Zeitschr. 
f.  allgem.  Physiologic  Bd.  VIII,   1908. 

2  Fillie :  "Studien  iiber  die  Erstickung  und  Erholung  des  Nerven  in  Fliissigkeiten." 
Zeitschr,  f.  allgem.  Physiologic  Bd,  VIII,   1908. 


THE  REFRACTORY  PERIOD  AXD  FATIGUE  1 


1 1 


say,  the  individual  alterations  produced  by  the  want  of  oxygen, 
that  is,  the  restriction  and  retardatic.n  of  the  oxydativc  disinte- 
gration, the  corresponding  increase  of  the  anoxydative  deconiiKj- 
sition  and  the  accumulation  of  the  products  of  incomj)letc  oxyda- 
tion  and  anoxydative  breaking  down  have  the  same  influence  in 
that  they  decrease  the  strength  of  the  response  and  retard  the 
rapidity  of  the  decomposition  ])rocess.  These  are  the  general 
effects  perceptible  in  the  refractory  period  by  the  deficiency  of 
oxygen. 

The  establishment  of  these  facts  of  the  dependence  of  the  re- 
fractory period  upon  oxygen  are  of  the  utmost  imi>ortance  for 
the  genesis  of  fatigue,  for  the  state  of  fatigue  in  all  aerobic  organ- 
isms is  invariably  brought  about  by  deficiency  of  oxygen.  In 
other  words:  fatigue  is  invariably  asphyxiation.  A  deficiency  of 
organic  reserve  substances  never  occurs  in  fatigue  l>eforc  the 
effect  of  oxygen  deficiency  leads  to  complete  depression,  for  the 
quantity  of  organic  reserve  substances  at  the  disposal  of  the  cells 
is  greater  comparatively  than  that  of  oxygen.  This  is  shown  by 
transfusion  experiments  in  which  the  time  involved  before  com- 
plete paralysis  was  brought  about  in  the  frog  by  the  introduction 
of  an  oxygen-free  saline  solution  was  ascertained  and  conii)ared 
with  the  period  which  elapsed  before  complete  paralysis  took 
place,  when  the  same  solution  saturated  with  oxygen  was  used. 

Although  the  previously  described  ex])eriments  on  the  strych- 
ninized  frog  show^  clearly  the  relations  of  fatigue  to  the  refractory 
period,  I  should,  nevertheless,  like  to  illustrate  them  somewhat 
further. 

The  state  of  fatigue  as  it  is  developed  in  a  living  system  by  a 
continuous  functional  activity  is  characterized  by  a  series  of 
symptoms  which  can  be  best  studied  in  the  fatigue  of  the  muscle. 
the  nervous  centers,  and  the  peripheral  nerves. 

If  the  muscle  of  the  frog  is  isolated  and  rhythmically  stimu- 
lated with  single  induction  shocks  and  the  muscle  contractions 
graphically  recorded,  it  will  be  found  that  the  first  perceptible 
alteration  during  the  course  of  stimulation  is  the  increasing 
height  in  the  curve,  which  ai)pears  directly  after  the  first 
contraction  and  becomes  more  and  more  noticeable  after  every 


178  IRRITABILITY 

succeeding  one.  With  the  isolated  apex  preparation  of  the 
frog's  heart  an  effect  is  produced  which  Bowditch^  has  termed 
the  "Treppe"  and  Tiegel/  Minof  and  others  have  obtained  the 
same  result  for  the  skeletal  muscle.  The  Treppe  has  been  often 
regarded  as  an  expression  of  increasing  of  capability  of  the 
muscle  following  each  succeeding  stimulus  in  spite  of  the  fact 
that  it  is  physiologically  incomprehensible  that  an  isolated  muscle 
can  become  more  capable  by  increased  demands.  Frohlich'^  first 
threw  light  on  this  seeming  contradiction  by  showing  that  the 
increase  in  height  of  the  muscle  contraction  in  the  Treppe  is 
in  reality  the  first  indication  of  the  beginning  of  fatigue,  and 
Fr.  Lee^  arrived  at  the  same  result.  The  increase  in  height  of  the 
contraction  curve  depends  upon  the  retardation  of  the  course  of 
contraction.  As  the  contraction  extends  over  the  muscle  sub- 
stance in  the  form  of  a  wave,  a  longer  stretch  of  the  muscle  will 
be  in  a  state  of  contraction  when  the  wave  is  more  extended  than 
when  it  is  shorter,  that  is,  the  shortening  of  the  muscle  will  be 
greater,  the  contraction  curve  higher,  when  the  wave  is  more 
extended.  With  increasing  fatigue  the  retardation  in  the  course 
of  contraction,  as  Rollet^  already  has  shown,  becomes  continu- 
ously greater.  (Figure  34.)  The  consequence  of  this  retardation 
in  the  course  of  contraction  is,  therefore,  perceptible  in  the 
rhythmically  activated  muscle  in  the  form  of  contracture.  As 
fatigue  increases,  the  muscle  requires  an  increasing  length  of  time 
to  relax  to  its  full  extent  and  in  consequence  the  period  between 
the  two  stimuli  is  very  soon  insufBcient  for  this  to  occur.    There 

1  Bowditch :  "Ueber  die  Eigenthiimlichkeiten  der  Reizbarkeit,  welche  die  Muskel- 
fasern  des  Herzens  zeigen."  Arbeiten  aus  der  physiologischen  Anstalt  zu  Leipzig  VI 
Jahrgang   1871,   Leipzig   1872. 

2  Tiegel:  "L^eber  den  Einfluss  einiger  willkiirlichen  Veranderungen  auf  die 
Zuckungshohe  des  untermaximal  gereizten  Muskels."  Arbeiten  aus  der  physiol. 
Anst.  zu  Leipzig  X  Jahrgang  1875,  Leipzig  1876. 

ZMinot:  "Experiments  on  tetanus."     Journ.  of  Anat.  and  Physiol.  Vol.   XII. 

4  Fr.  W.  Frohlich:  "Ueber  die  scheinbare  Steigerung  der  Leistungsfahigkeit  des 
quergestreiften  Muskels  im  Beginn  der  Ermiidung.  (Muskel  Treppe),  der  Kohlen- 
saurewirkung  und  der  Wirkung  anderer  Narcotica  (Aether,  Alkohol)."  Zeitschr.  £. 
allgem.    Physiologic   Bd.   V,    1905. 

5  Frederic  S.  Lee:  "The  cause  of  the  Treppe."  Americ.  Journ.  of  Physiol.  Vol. 
XVIII.  1907. 

6  Alexander  Rollet:  "Ueber  die  Veranderlichkeit  des  Zuckungsverlaufs  quer- 
gestreifter  Muskeln  bei  fortgesetzter  periodischer  Erregung  und  bei  der  Erholung 
nach  derselben."     Pfliigers  Arch.  Bd.  64,  1896. 


180  IRRITABILITY 

remains  a  certain  amount  of  shortening,  when  the  next  contraction 
begins.  This  characteristic  extension  of  the  individual  contraction 
curve  of  the  fatigued  muscle  is  an  expression  of  the  retardation 
of  the  oxydative  disintegrating  processes  and  of  the  Treppe,  It 
shows  us  that  fatigue  is  perceptible  to  a  slight  degree  even  after 
the  first  excitation.  After  every  succeeding  stimulus  the  oxyda- 
tive decomposition  in  the  fatigued  muscle  is  increasingly  pro- 
longed. It  is,  therefore,  self-evident  that  the  capability  of  action 
of  the  muscle  likewise  becomes  less  with  increasing  fatigue. 
Every  state  of  fatigue  is,  in  fact,  distinguished  by  the  decrease  of 
response.  This  is  perceptible  in  the  later  stages  by  the  decline  of 
the  height  of  contraction.  Hence  all  symptoms  of  fatigue  which 
we  observe  form  the  expression  of  one  single  process;  it  is  the 
constantly  increasing  slowness  of  oxydative  disintegration  with 
increasing  fatigue. 

Exactly  similar  conditions  as  those  of  the  muscle  are  seen  in 
the  central  nervous  system.  The  reflex  contraction  of  the  triceps 
of  the  frog  produced  by  stimulation  of  the  central  end  of  the 
sciatic  nerve  with  single  induction  shocks  demonstrates  clearly 
as  Ishikawa}  has  proved  in  certain  stages  of  fatigue,  an  increase 
in  height  and  a  strong  relaxation  which  does  not  depend  upon  the 
fatigue  of  the  muscle  but  on  that  of  the  centers.  If  the  fatigue 
is  greater,  the  height  of  the  contraction  then  decreases,  whereas 
the  extension  of  the  course  of  relaxation  increases  further.  The 
possibility  of  fatigue  of  the  muscle  during  these  experiments  was, 
of  course,  precluded  by  proper  precautionary  measures.  Irri- 
tability and  the  course  of  excitation  in  fatigue  of  the  centers 
show  exactly  the  same  alterations  as  developed  in  fatigue  of  the 
muscle.  The  processes  of  oxydative  breaking  down  are  retarded 
more  and  more  with  increasing  fatigue,  that  is,  fatigue  is  charac- 
terized by  exactly  the  same  processes  as  is  the  prolongation  of 
the  refractory  period  by  the  deficiency  of  oxygen,  and  likewise 
in  fatigue  this  retardation  of  the  oxydative  disintegration  pro- 
cesses is  conditioned  by  the  relative  deficiency  of  oxygen.  This 
is  shown  by  the  role  played  by  oxygen  in  recovery  after  fatigue. 

1  Hidetsurumaru  Ishikawa:  "Ueber  die  scheinbare  Bahnung."  Zeitsclir.  f.  allgem. 
Physiologic  Bd.   XI,   1910. 


THE  REFRACTORY  PERIOD  AND  FATKiL'E     181 

It  was  found  by  Hermann^  in  18(17  and  confirnicd  by  Mademoi- 
selle Jotcyko'^  in  Richct's  laboratory,  that  the  isolated  nuisclc  of 
the  frog,  which  was  c()nii)lL'tely  nonirritable  as  the  result  of 
fatigue,  does  not  regain  irritability  in  an  oxygcn-frcc  medium, 
but  does  so  when  oxygen  is  introduced.  The  i)reviously  de- 
scribed experiments  of  artificial  circulation  in  the  frog  show 
clearly  how  dependent  the  centers  are  upon  the  oxygen  suj)ply 
for  the  restoration  of  irritability.  In  consequence  of  the  strych- 
nine poisoning  the  irritability  of  the  centers  is  so  enormously 
increased  that  the  *'all  or  none  law"  is  aj)plicable  to  the  centers  of 
the  spinal  cord  under  these  conditions.^  These  are  the  l>cst  condi- 
tions for  the  production  of  fatigue.  One  can  readily  demonstrate 
the  importance  of  the  oxygen  supply  for  the  ra{)idity  with  which 
irritability  returns  after  fatigue  if  in  the  strychninized  frog  an 
artificial  circulation  is  used,  at  the  same  time  varying  on  one  hand 
the  amount  of  oxygen,  on  the  other  the  activity  of  the  centers.  If 
a  saline  solution  containing  merely  a  trace  of  oxygen  is  circulated. 
the  centers  recover  very  slowly  and  incompletely  after  every 
fatigue.  Subsequent  to  every  reaction  ])r()(luced  by  a  stinuilus, 
an  increasing  length  of  time  is  required  until  irritability  is  so  far 
recovered  that  a  new  stimulus  can  meet  with  response.  If.  how- 
ever, a  saline  solution  is  circulated  which  has  been  saturated  l)y 
being  shaken  with  oxygen  and  is  continuously  in  a  ])urc  atmos- 
phere of  oxygen,  recovery  takes  ])lace  in  comj)arison  with  far 
greater  rapidity  and  completeness.  If  the  supi)ly  of  oxygen  is 
ample  and  the  stimuli  act  at  longer  intervals  on  the  frog,  irri- 
tability always  is  quickly  restored  in  the  i)erio(ls  of  rest  l>etween 
the  stimuli.  With  continuous  stimulation  of  quickly  succeeding 
stimuli,  irritability  is  soon  completely  obliterated,  even  th«»ugh  an 
abundant  oxygen  supply  be  present,  and  it  is  not  until  a  pause  is 
interpolated  that  oxygen  is  capable  of  bringing  about  a  recovery. 
By  manifold  variations  of  these  experiments  the  connection 
between  fatigue  and  the  refractory  period  can  be  more  and  more 

\  Hermann:   "Untersiichungcn   iil.cr   tk-n    StotTwcchscl   -Irr    Mnskcln   •unrchcnd   T.-m 

Gaswechsel  dersclben."      Berlin    1867. 

2Jotcyko:  "La  fatigue  et  la  respiration  elcmentaire  du  muscle."     Pan*   iv 
i  Julius   Veszi:  "Zur   Frage   des  .Mies  oder  Nichts  ('.c»etie»  beim  Strychn. 

Zeitschr.   fur  allgem.    Physiologic   Bd.    XII.    1911. 


182  IRRITABILITY 

clearly  recognized.  Fatigue  is  simply  the  refractory  period  pro- 
longed by  deficiency  of  oxygen.  In  both  cases  there  is  a  diminu- 
tion of  irritability.  In  both  cases  this  diminution  is  conditioned 
by  a.  retardation  of  oxydative  disintegration  following  every 
stimulation.  In  both  cases  it  is  the  relative  deficiency  of  oxygen 
which  produces  this  delay.  In  both  cases  the  oxydative  decompo- 
sition can  be  quickened  and  irritability  restored,  that  is,  the  refrac- 
tory period  lessened  and  fatigue  removed  by  a  sufficient  supply  of 
oxygen.  The  amount  of  oxygen  which  suffices  to  constantly  main- 
tain the  specific  irritability  of  a  living  system  in  an  undisturbed 
metabolism  of  rest  is  not  sufficient  if  the  system  is  continuously 
functionally  activated  by  stimulation.  The  refractory  period 
increases  after  excitation  and  merges,  although  very  gradually, 
finally  into  permanent  nonirritability,  that  is,  into  complete 
fatigue. 

The  knowledge  that  fatigue  represents  a  prolonged  refractory 
period  resulting  from  relative  deficiency  of  oxygen  has  enabled 
me  with  the  aid  of  my  coworkers  to  demonstrate  the  existence 
of  fatigue  and  produce  the  typical  symptoms  experimentally  for 
a  living  tissue,  which  up  to  then  was  considered  indefatigable: 
I  refer  to  the  medullated  nerve.  After  having  found  that  the 
condition  necessary  for  the  production  of  fatigue  in  the  nervous 
centers  is  a  deficiency  of  oxygen,  I  arrived  at  the  conclusion  that 
fatigue  could  only  be  obtained  in  the  medullated  nerve  when  sub- 
jected to  a  deficiency  of  oxygen.  Up  to  that  time,  however,  no 
consumption  of  oxygen  was  known  for  the  nerve.  It  was,  there- 
fore, necessary  to  first  ascertain  if  the  nerve  possessed  an  oxyda- 
tive metabolism.  At  my  request,  H.  von  Baeyer  investigated  these 
questions.  After  many  vain  attempts  to  obtain  absolutely  pure 
nitrogen,  we  finally  succeeded  in  finding  a  method  by  which  it  is 
possible  to  gain  nitrogen  gas,  which  is,  one  might  almost  say,  in 
a  mathematical  sense  absolutely  pure.  It  was  then  possible  for 
H.  von  Baeyer'^  to  asphyxiate  the  nerve  and  subsequently  to  bring 
about  complete  restoration  by  the  introduction  of  oxygen.  It 
was  shown  that  the  nerve  requires  merely  a  minute  quantity  of 

1  Hidetsurutnaru  Ishikawa:  "Ueber  die  scheinbare  Bahnung."  Zeitschr.  f.  allgem. 
Physiologic  Bd.  Ill,  1904. 


THE  REFRACTORY  PERIOD  ANT)  FATIGUE     183 

oxygen  and  only  completely  asi)hyxiales  when  the  last  trace  of 
oxygen  is  removed,  and  further  that  recovery  takes  place  within 
a  fraction  of  a  minute  if  the  oxygen  is  again  supplied.  These 
experiments  which  have  been  carried  further  hy  ProhlicIO  were 
afterwards  confirmed  in  other  laboratories.-  and  form  the  basis 
for  proving  the  existence  of  fatigue  of  the  medullated  nerve. 
Shortly  after,  Frohlich^  was  able  to  demonstrate  symptoms  of 
fatigue  in  the  medullated  ner\e.  He  found  that  the  refractory 
period  of  the  nerve,  which,  as  previously  mentioned,  Gotch  and 
Burch  fixed  at  about  .005  second  duration,  was  prolonged  by 
oxygen  deficiency  to  .1  second,  so  that  stimuli  following  each 
other  oftener  than  ten  times  per  minute  produced  merely  single 
initial  contractions  in  the  muscle  concerned,  that  is,  in  a  series 
of  stimuli  of  which  the  intervals  are  less  than  .1  per  second,  only 
the  first  produces  response,  whereas  the  following  occur  in  the 
refractory  period,  brought  about  by  those  preceding,  and  arc, 
therefore,  inoperative.  The  nerve  is  fatigued  by  the  (juick  suc- 
cession of  stimuli.  The  normal  nerve  on  the  contrary  invarial)ly 
responds,  as  knowni,  to  an  even  more  rapid  succession  of  stimuli 
with  a  rhythmical  excitation  corresponding  to  the  number  of 
stimuli  and  which  is  manifest  in  the  muscle  by  a  tetanus.  This 
again  confirmed  the  identity  of  fatigue  with  the  prolonged  re- 
fractory period,  conditioned  by  the  relative  want  of  oxygen.  It 
likewise  explained  the  conditions  of  the  analogous  behavior  that 
Wedensky^  had  observed  in  the  narcotized  nerve,  but  had  neither 

\  Fr.    W.    Frohlich:   "Das    Sauerstoffbedurfniss    des    Ncrvcn."      Zeitscbr.    f.    allfrtn. 

Physiologic  Bd.  Ill,    1904. 

2  K.    H.    Baas:    "Zur    Frage    nach    dem    SauerstofThcdiirfniss    dcs    Fro»chncnren." 

Pflugers  Arch.   Bd.   103,    1904. 

K.  Prick:  "Die  Abhangigkeit  der  Erregbarkcit  dcs  i»criphcri»chcn  Ncnrrn  vom 
Sauerstoff."  Inaugural  Dissertation  vorgelegt  dcr  mcdicinischcn  Facullat  der  I'niTcr*. 
Berlin   (Aus  dem  physiologischen   Institut  dcr  Univcrs.).      Berlin    1904. 

Uchtomsky  und  Dcrnoff:  "Zur  Frage  nach  dem  SaucrstofT»)cdiJrfniM  dcr  Ncrvcti  " 
Travaux    du    laboratoire    de    Physiologic    a    I'univcrsitc    dc    St.    Prtrf -ihotirK    II    .\niirc 

1907. 

3  Fr.    W.   Frohlich:  "Die  Ermiidung  dcs  markhaltigen  Ncrvcn."     ZcHKrhr.  f.  »IIgrm. 

Physiologic   Bd.    Ill,    1904. 

AlVedensky:       "Die  fundamcntalen     Eigcnschaftcu    dts    .Ncrvcn    untcr    Kinwirkung 

einiger  Cifte."     Pflugers  Arch.  Bd.  82,    1900. 

The   same:    "Erregung,    Hcmmung   und    Narkosc."      In    the   name    pUc*.      Bd.    100. 

1903. 


184 


IRRITABILITY 


recognized  as  manifestation  of  the  prolonged  refractory  period 
nor  as  fatigue.  A  further  advance  was  made  by  the  investigations 
of  Thorner.  He  placed  two  nerves  of  the  same  frog  in  a  double 
chamber  under  completely  identical  conditions  with  the  excep- 
tion that  one  remained  in  a  state  of  rest,  whilst  to  the  other 
tetanic  stimuli  were  applied.     (Figure  35.)     If  this  took  place  in 


ji 


TX 


"T  VBSI8 


Fig.  35. 

Double  glass  chamber  for  comparative  experiments  on 
fatigue  of  the  nerve  in  n).  A  and  B— Wires  of 
the  electrodes.    (After  Thorner.) 


nitrogen,  the  irritability  of  the  stimulated  nerve  invariably  sank 
with  much  greater  velocity  than  that  of  the  nonstimulated,  where- 
as after  an  introduction  of  oxygen,  even  when  the  stimulation  was 
continuous,    both    again    recovered.      In    these    experiments    of 


THE  REFRACTORY  PERIOD  AND  FATIGUE     185 

Thorner'  the  action  current  and  not  the  nuiscle  contraction  served 
as  indicator.  Here  the  fatigue  of  the  nicihillaled  nerve  brought 
about  by  the  deficiency  of  oxygen  during  prolonged  stimulation 
is    demonstrated    in    the    most   obvious    manner.      (Figure    36.) 


2 

<^ 

^ 

■ 

r — 

\ 

— 

... 

.,- 

— 

._. 

"'' 

/ 

^ 

S 

^  — 

-- 

^  ^ 

n-' 

"7 

fi 

\ 

/ 

X 

V 

\ 

--H 

^ 

"K 

} 

\ 

k 

/ 

1 

^ 

r 

1 — 

tN 

J 

0.5 

—  «. 

"itu 

kst 

^JT 

_^ 

^au 

KTii 

-^ 

"tic 

r— ) — ' 
kstojf- 

1 

_Sausrst 
1 

0.0 

^ 

V 

;. 

V 

I 

V 

; 

v 

i 

3 

v 

S^ 

Xr 

41 

Fig.  36. 
Curve  of  action  current  of  two  nerves,  one  of  which  is  stimu- 
lated (plain  line  I  whilst  the  other  remains  at  rest  di>tted 
linei.  After  decrease  of  irritability  of  the  stimulated  nerve 
in  nitrogen,  oxygen  is  introduced  into  the  chamber  and 
irrritability  increases  again.  Then  the  previously  resting 
nerve  is  stimulated  in  nitrogen  and  the  stimulated  nerve 
remains  at  rest.     (After  Thorner.) 

Thorner-  further  succeeded  by  a  continuous  stimulation  of  the 
nerve  in  obtaining  even  in  atmospheric  air  the  indications  of  pri- 
mary fatigue.  The  symptoms  were  exactly  the  same  as  those 
characterizing  fatigue  of  the  muscle;  the  extension  of  the  course 
of  excitation  and,  as  a  consequence  of  this,  the  appearance  of  a 
summation  of  excitation  produced  by  tetanic  currents  and  a  re- 
duction of  irritability  in  response  to  single  stimuli.  The  form  of 
the  curve,  resulting  from  alteration  of  irritability  in  fatigue  and 
recovery,  likewise  shows  complete  conformity  with  that  of  the 
muscle.  (Figure  37.)  Finally  Thorner  proved  that  tlie  nerve, 
when  fatigued  by  continuous  tetanic  stimulation  in  nitrogen, 
could  also  partially  recover  in  the  latter  if  the  stimulation  was 

iTIwrticr:  "Die  Ermiidung  des  markhaltigen  Nervcn."  Zcitschr.  f.  aliKfni  i'n)»i- 
ologie  Bd.  VIII,   1908. 

2  Thorner:  "Weitere  Untersuchungen  ijber  die  Krmiidung  dcs  markhaltigrn  Nerren. 
Die  Ermiidung  in  Luft  und  die  scheinharc  ErrcgharkcitMtcigcrung."  Zrilachr.  f. 
allgcm.    Physioiogie   Hd.    X,    1910. 

3  Thorner:  "Weitere  Untersuchungen  iihcr  die  Krmudung  dr»  markhalligrn  Nervcn 
Die  Ermiidung  und  Erholung  unter  Ausschluss  von  SaucrstofT."  Zeittchr.  (.  tllgcm 
Physioiogie    Bd.    X.    1910. 


186  IRRITABILITY 


■Maaa 


\ 


*_ 


Scheme  showing  course  of  fatigue  (plain  line)  and  recovery  (dotted  line)  of  the  nerve 
as  it  is  manifested  on  testing  the  irritability  with  tetanic  stimuli,  when  fatigue  and 
recovery  alternate  at  equal  intervals.  The  curve  shows  at  the  beginning  an  apparent 
increase  of  irritability  corresponding  to  the  "Treppe"  of  the  muscle.    (After  Thomer.) 


y 
/ 
/ 
/ 
/ 
/ 
/ 
t 
I 
I 
I 
I 


B 
Fig.  37. 

Scheme  showing  course  of  fatigue  (plain  line)  and  recovery  (dotted  line)  on  testing  the 
irritability  of  the  nerve  by  single  induction  shocks.  In  fatigue  irritability  sinks  at  first 
rapidly,  then  more  and  more  slowly  until  a  state  of  equilibrium  is  reached.  Recovery 
shows  the  same  in  reverse  succession.    (After  Thomer.) 

interrupted,  whereas  a  complete  recovery  could  not  take  place 
unless  a  supply  of  oxygen  was  introduced.  (Figure  38.)  This 
fact  is  in  perfect  accordance  with  the  relations  found  by  Ver- 
worn,  Lipschiitz,  in  fatigue  of  the  nervous  centers.  It  is  the 
expression  for  the  accumulation  and  removal  of  fatigue  sub- 
stances, the  depressing  effect  of  which  Ranke'^  first  established 
for  the  fatigued  muscle.  The  fact  that  the  nerve  could  also  par- 
tially recover  in  an  atmosphere  of  nitrogen  would  seem  to  like- 
wise contain  the  proof  that  among  the  fatigue  substances  products 
in  the  form  of  gas  must  be  present.  It  is  probable  that  an  escape 
of  carbon  dioxide  has  taken  place. 

1  Ranke:   "Untersuchungen    tiber   die   chemischen   Bedingungen    der   Ermiidung   des 
Muskels."     Arch.   f.   Anat.    u.    Physiol.    1863   u.    1864. 


THE  REFRACTORY  PERIOD  AXlJ  FATIGUE     187 

As  a  result  of  all  these  investigations,  linked  together  in  a  5)3- 
tematic  series,  the  proof  has  now  been  obtained  that  ilie  nerve 
like  all  other  living  substances  is  fatigable.  its  fatigue  is  solely 
the  manifestation  of  a  prolonged  refractory  period  and  the  exten- 
sion of  the  latter  by  continuous  stinuilation  is.  as  in  all  aerobic 
substances,  a  result  of  relative  deficiency  of  oxygen. 


WO 


CL 

200 


300 


kOO 


Stick  stuff' 


Scuwr  staff 


o5« 


w 


Fig.  38 


30 


tfO 


50 


rv 


Curve  of  irritability  as  demonstrated  by  action  current  of  two  nerves 
in  nitrogen,  which  are  alternatively  stimulated  plain  line  and  at 
rest  (dotted  line'.  Recovery  in  nitrogen  is  always  merely  partial 
and  relative.  It  only  increases  on  introduction  of  oxygen.  '  AUcr 
Thorner.) 


To  briefly  summarize  in  conclusion,  I  will  rej)eai  that  just  as 
all  living  systems  show  a  refractory  j)erio(l  after  an  excitation,  in 
which  irritability  is  reduced,  all  living  systems  are  likewise  capable 
of  fatigue.  Both  are  most  intimately  connected  and  are  based 
fundamentally  on  the  facts  of  metabolism. 

An  excitating  stimulus  disturbs  the  metabolic  equilibrium  of 
rest  by  suddenly  bringing  about  increa.sed  decomi)osition  of  cer- 
tain substances.  During  and  directly  after  the  breaking  down, 
irritability  is  reduced  in  the  same  degree  as  the  amount  of  siil>- 
stances  required  for  disintegration  in  response  to  a  succeeding 
stimulus    is    decreased    and    the    (juantity    of    the    decomposition 


188  IRRITABILITY 

products  is  increased.  This  is  the  refractory  period.  By  the 
metaboHc  self-regulation  in  accordance  with  the  principle  of 
chemical  equilibrium,  the  original  metabolic  equilibrium  is 
restored  after  every  excitation.  Irritability,  therefore,  increases 
in  the  same  measure  as  this  occurs,  that  is,  in  the  form  of  a 
logarithmic  curve,  until  it  again  reaches  the  specific  degree  of 
irritability  of  the  particular  system.  The  refractory  period 
diminishes.  If  the  processes  of  disintegration  and  self-regulation 
are  delayed,  either  by  want  of  substance  necessary  for  breaking 
down  or  the  accumulation  of  decomposition  substances,  the 
refractory  period  is  prolonged  and  the  response  to  every  further 
stimulation  decreased,  that  is,  the  system  is  fatigued.  In  all 
aerobic  organisms  the  retardation  of  the  course  of  excitation  and 
self-regulation  under  a  continuous  influence  of  stimuli  is  the  result 
of  the  relative  want  of  oxygen.  The  processes  of  oxydative  dis- 
integration are  prolonged  and  restricted  by  relative  deficiency  of 
oxygen  and  merge  more  and  more  into  anoxydative  decomposi- 
tion. The  products  of  incomplete  oxydative  and  anoxydative 
decomposition  accumulate.  Both  factors  decrease  the  strength 
of  the  response  after  every  stimulation.  Thus  the  want  of  oxygen 
leads  to  reduced  activity.  In  the  anaerobic  organisms  the  refrac- 
tory period  and  symptoms  of  fatigue  are,  of  course,  produced  by 
the  relative  deficiency  of  other  substances.  Fatigue  in  the 
anaerobic  systems  has,  however,  so  far  not  been  investigated.  We 
advance  very  slowly,  step  by  step,  in  physiology,  and,  as  in  every 
science,  an  acquirement  of  a  new  knowledge  means  a  new  prob- 
lem. In  this  lies  the  inexhaustible  charm  of  our  scientific 
research. 


CHAPTER    \III 
INTERFERENCE  OF  EXCITATION'S 

Contents:  Examples  of  effects  of  interference  of  stimuli  in  unicellular 
organisms.  Interference  of  galvanic  and  thermic  stimuli  in  Para- 
mecia.  Interference  of  galvanic  and  thermic  stimuli  and  narc«ilics. 
Interference  of  galvanic  and  mechanical  stimuli.  Interference  of  gal- 
vanotaxis  and  thigmotaxis  in  Paramecia  and  hypotrii  infusoria.  Real 
or  homotop  interference,  apparent  or  hcterotop  interference.  The 
two  effects  of  homotop  interference  of  excitations:  Summation  and 
inhibition  of  excitations.  Theory  of  the  processes  of  inhibition. 
Hering-Gaskell  theory.  Inhibition  as  an  expression  of  the  refractory 
period.  Individual  possibilities  of  interference  of  two  stimuli.  Inter- 
ference of  an  excitating  and  a  depressing  stimulus.  Interference  of 
two  depressing  stimuli.  Interference  of  two  excitating  stimuli. 
Analysis  of  the  interference  of  two  excitations.  Interference  of  two 
single  stimuli.  Conditions  upon  which  the  result  of  interference  is 
dependent.  Heterobole  and  isobole  living  systems.  Intensity  of  the 
two  stimuli.  Interval  between  the  stimuli.  Specific  irritability  and 
rapidity  of  reaction  of  the  living  system.  Latent  i)eriod.  Interference 
of  single  stimuli  in  a  series.  General  scheme  of  the  development  of 
the  effect  of  interference.  Summation  and  inhibition.  .Apparent 
increase  of  irritability.  Conditions  of  summation.  Tonic  excitations. 
Conditions  of  inhibition.  Various  types  of  inhibition.  Interference 
of  two  series  of  stimuli.  Relations  in  the  nervous  system.  Peculiari- 
ties of  the  nerve  fibers.  Conversion  of  the  nerve  by  relative  fatigue 
from  an  isobolic  into  a  heterobolic  system. 

Until  now  the  mechanism  of  the  .'tingle  excitation  has  received 
the  major  portion  of  our  attention.  It  was  iu)t  initil  we  reached 
the  subject  of  the  origin  of  fatigue  that  we  became  acijuaintetl 
with  the  effects  of  repeated  stimulation.  Here  we  fi)und  a  case 
of  interference  of  individual  excitations.  lUit  fatigue  is  dimply 
a  special  instance  of  such  interference,  for  tlic  subject  of  inter- 
ference action  occupies  a  much  greater  field. 

Every  cell  of  the  larger  organisms,  and  more  esi>ccially  the 
single  celled  organisms,  is  subjected  to  manifold  stinuili.     It  is 


190 


IRRITABILITY 


indeed,  quite  common  that  two  stimuli  interfere  with  each  other 
and  manifold  effects  follow,  depending  upon  the  specific  reaction 
of  the  cell  and  the  quality,  intensity  and  duration  of  the  inter- 
fering stimuli.  Sometimes  the  interference  effect  is  readily 
understandable  from  a  knowledge  of  the  specific  effect  of  the 
individual  stimuli  concerned.  At  other  times,  however,  the 
specific  reaction  seems  entirely  different  in  nature  than  would 
be  expected  from  a  study  of  the  effects  of  the  individual  stimuli. 


Fig.  39. 
Galvanotaxis  of  Paramaecium  aurelia. 


When  I  place  a  drop  of  Paramecium  culture  on  a  slide  having 
on  two  sides  parallel  pieces  of  baked  clay  which  serve  as  elec- 
trodes and  allow  a  constant  current  of  about  .2  milliampere  to 
flow  through,  it  will  be  seen  that  the  infusoria  at  room  tempera- 
ture move  toward  the  negative  pole  at  a  rate  averaging  1-1.4  mm. 
per  second.  (Figure  39.)  If  I  increase  the  temperature,  the  rate 
of  movement  is  increased.  Here  the  galvanic  and  the  thermal 
stimuli  influence  each  other  in  such  a  manner  that  the  reaction 


INTERFKRRNCE  OF  KXCITATIOXS  191 

to  the  galvanic  is  increased  In-  the  thernial  stimulation.  This 
summation  of  excitation  is  readily  understood  on  the  hasis  of  the 
laws  conccrninn^  the  eilect  of  tcnii)crature  upon  the  velocity  of 
chemical  change  established  by  ra;/'/  1 1  off.  If.  however,'  the 
Paramecia  are  in  a  1  i)cr  cent,  alcoholic  solution,  then,  as  was 
shown  by  Nagai,'  the  rai)i(lity  of  movement  following'  jjalvanic 
stimulation  is  decidedly  reduced.  The  interference  effect  Inrtween 
the  galvanic  and  chemical  stimulati(jn  is.  because  of  the  depressing 
effect  of  the  latter,  likewise  readilv  understood. 


Fig.  40. 
Thigmota.xis  of  Paramaecium  aurelia.     i  .After  Jennings. ' 

Greater  difficulty  meets  us,  however,  in  the  following  instance. 
The  forward  movements  of  the  Paramecia  follow  in  conse(|uence 
of  the  fact  that  the  individual  cilia  of  the  body  lash  more  ])ower- 
fully  backward  than  forward.  If  now  the  Paramecia,  while 
moving  forward,  meet  with  a  resisting  body,  they  withdraw  side- 
ways while  executing  a  sudden  strong  forward  ciliary  stroke.  The 
strong  mechanical  stimulation  brings  about  retraction  of  the 
organism.  Entirely  different  are  the  results  when  the  impact  is 
weak.  If  Paramecia  while  slowly  swimming  touch  a  resisting 
object  with  the  anterior  ])ortion  of  the  body,  withdrawal  does  not 
occur.  The  infusoria  remain  under  proper  conditions  in  contact 
with  the  resistance,  and  the  rhythmic  activity  of  the  cilia  directly 
against  resistance,  as  well  as  those  on  the  other  side  toward  the 
posterior  portion  of  the  body,  arc  mnrc  or  less  inhibited.  I  Figure 
40.)  The  degree  of  inhibition  brought  about  by  this  weak 
mechanical  stimulation  may  vary  considerably.     .\t  times  the  cilia 

1  Nagai:  "Der   Einfluss  vcrschiedcner  Narcotica.  (lasc  und   Salzc  auf  die  Schwi 
geschwindigkcit  von   Paramecium."     Zeitschr.   f.  allgcm.    Physiologic  Bd.   VI.   1907. 


192 


IRRITABILITY 


of  the  whole  body  suddenly  cease  their  movement.  (Figure  41, 
A.)  At  other  times,  this  cessation  is  Hmited  to  the  cilia  in  the 
anterior  portion  of  the  body  (Figure  41,  B),  while  the  movements 
of  those  on  the  posterior  portion  of  the  body  are  of  less  amplitude 
or  are  irregular  and  weak.  In  all  cases  the  infusorium  remains 
quiescent  in  the  water  in  contact  with  the  resistance,  and  it  is  not 
uncommon  to  find  numerous  individuals  in  apposition  with 
particles  of  ground,  slimy  detritus,  plant  fibers  and  so  forth. 
(Figure  41,  C.)     In  short,  the  rhythmic  activity  of  the  cilia  of 


B 

Fig.  41. 
Thigmotaxis  of  Paramaecium  aurelia. 


the  Paramecia  receiving  their  normal  impulses  of  excitation  from 
the  ectoplasm  of  the  cell  body  interfere  with  strong  mechanical 
stimuli  in  such  a  manner  that  a  negative  thigmotaxis  develops ; 
following  weak  mechanical  stimuli  a  positive  thigmotaxis  results. 
Here  is  an  instance  of  the  relation  between  the  intensity  of  the 
stimulus  and  the  manner  in  which  its  effects  interfere  with  an 
already  existing  excitation. 

However,  the  strength  of  the  inhibitory  effect  of  a  weak  con- 
tact stimulus  upon  another  excitation  is  best  appreciated  when 


INTERFERENCE  OF  EXCITATIONS  193 

positive  thigiiiotaxis  is  interfered  with  by  the  effect  of  a  tliernuil 
or  galvanic  stimulus.  Joinings^  and  especially  Putter-  have,  at 
my  request,  more  thoroughly  investigated  my  original  observa- 
tions and  have  given  us  a  complete  analysis  of  these  interesting 
interference  effects.  If  the  freely  swimming  Paramecia  are  sub- 
jected to  a  constantly  increasing  temperature,  the  movements  of 
these  infusoria  become  more  and  more  active.  At  30°  C..  the 
rapidity  is  very  violent  and  at  about  37°  C.  they  rcacii  their  maxi- 
mal. If  now  the  same  experiment  is  repealed  with  Paramecia 
vv^hich  have  in  consequence  of  thigmotaxis  lixed  themselves  to 
particles  of  slime,  the  temperature  may  be  increased  to  30**  C. 
without  an  observable  effect.  The  infus(»ria  remain  througliout 
in  contact  with  the  resistance.  Only  when  the  tem])erature  is 
37°  C.  do  they  release  their  contact  and  move  violently  through 
the  water.  If  a  drop  containing  Paramecia  is  i)laced  on  a  slide, 
between  parallel  pieces  of  fired  clay  which  serve  as  electrodes, 
it  will  be  seen  that  some  freely  swim  about,  whereas  others 
remain  thigmotactically  in  contact  with  j^articles  of  slime.  When 
a  constant  current  of  about  .2  of  a  milliam])ere  is  passed  through, 
it  is  observed  that  the  freely  swimming  individuals  hasten 
towards  the  cathode.  Those  attached  to  objects,  on  the  con- 
trary, do  not  respond  in  this  manner  to  the  electrical  current. 
(Figure  42.)  The  intensity  of  the  current  can  be  greatly  in- 
creased without  bringing  about  detachment  of  the  individuals 
from  their  position  of  fixation.  The  typical  intlucnce  of  the 
strong  current  upon  the  movement  of  the  cilia  of  the  thigmotacti- 
cally fixed  individuals  can  be  clearly  seen.  Xevertheless.  the 
inhibition,  brought  about  by  the  contact  stimulus,  predominates 
over  that  of  the  excitating  effect  of  the  current,  so  that  a  freeing 
of  the  organisms  from  their  position  does  not  occur.  Xot  until 
the  current  becomes  very  strong  is  the  excitation  thereby  pro- 
duced sufficient  to  bring  about  a  separation  of  the  infusoria, 
whereupon  they  immediately  swim  toward  the  cathode.     In  this 

1  Herbert   S.   Jennings:  "Studies  on   reactions  to   stimuli   in    uniccllul.ir        .-    - 
I.   Reactions    to    chemical,    osmotic    and    mechanical    stimuli    io    ih«-    cili.itc 

Journal   of   Physiology,   Vol.   XXI.    189  F.  ,         .   , 

2  putter:   "Studien   iiber   Thigmotaxis  bci    Protistcn."     .\rch.    i.    .\nat.    und    I  hywol- 

ogie,  physiol.  Abt.  Suppl.   1900. 


194 


IRRITABILITY 


interference  between  the  contact  stimulus,  on  the  one  hand,  and 
the  thermal  or  galvanic  on  the  other,  the  inhibitory  effect  of  the 
former  may  overpower  the  strong  excitation  of  the  latter. 


Fig.  42. 

Interference  of  galvanotaxis  and  thigmotaxis  in  Paramaecium  aurelia.  The 
individuals  which  are  thigmotactically  attached  to  sHme  particles 
remain  at  rest  while  the  freely  swimming  individuals  move  toward  the 
cathodic  pole. 


Still  more  complex  and  striking  is  finally  the  following  case 
of  interference  between  thigmotaxis  and  galvanotaxis.  The 
hypotrichous  infusoria  as  Stylonychia,  Urostyla,  Oxytricha,  etc., 
have  a  marked  functional  and  morphological  differentiation  of 
their  cilia.  They  possess  a  bow-like  row  of  perioral  cilia,  which 
sweep  in  the  food ;  a  number  of  cilia  on  the  ventral  surface  used 
for  locomotion  by  which  they  move  about  upon  objects  in  the 
water ;  a  row  of  border  cilia  on  each  side,  which,  during  swim- 
ming,  contribute  the  propelling   force.     The  perioral   cilia   also 


INTERFERENCE  OF  EXCITATIONS 


195 


form  the  elements  which  hring  al)out  a  screw-like  movement  on 
the  axis.  They  further  ])ossess  several  cilia,  which  jiermit  a  re- 
bounding of  the  organism,  and  fmally  certain  forms  have  anal- 
cilia,  which  probably  serve  as  breaks  and  lu  steer  the  organism. 
(Figure  43.)  Their  usual  mode  of  locomotion  is  that  of  creep- 
ing, moving  by  means  of  the  cilia  on  the  ventral  surface.  These 
movements  dei)en(l  upon  the  positive  thigmota.xis  of  the  cilia  of 
locomotion.     At  the  same  time  there  is  inhibition  of  the  cilia  on 


A  B 

Fig.  43. 

Hypotrichous  infusoria.    A— Stylonychia.    B— Urostyla. 


the  sides.  When  the  infusoria  are  excitated  by  a  new  stimulus, 
the  cilia  used  for  rebounding  become  active,  the  body  frees  itself 
from  its  position  of  attachment  and  begins  to  swim,  wherein  the 
cilia  on  the  sides,  as  well  as  the  perioral  cilia,  act  in  the  manner 
mentioned  above.  I  have  made  the  striking  observation  that  the 
hypotrichous  infusoria  respond  dilTerently  to  the  galvanic  cur- 
rent, depending  on  whether  they  are  swimming  or  in  a  fixed 
position.  If  one  places  a  drop  of  water  with  numerous  L'rostyla 
on  a  slide  between  parallel  pieces  of  fired  clay  which  serve  as 
electrodes,  it  will  be  seen,  upon  the  closing  of  a  current,  that  all 


196 


IRRITABILITY 


of  the  individuals  which  are  freely  swimming  and  turning  in 
a  screw-like  manner  around  their  axis,  steer  immediately  toward 
the  cathode,  exactly  as  in  the  case  of  the  Paramecia.  On  the 
other  hand,  those  which  are  fixed  to  the  bottom  of  the  slide  as 
a  result  of  thigmotaxis,  upon  closing  of  the  current,  make  a  short 
turn  and  assume  a  position  wherein  the  long  axis  is  at  right 
angles  to  the  direction  of  the  current,  and  the  perioral  rim  is 
directed  toward  the  cathode.  In  this  position  they  move  through 
the  field.     (Figure  44.)     When  the  current  is  broken  the  indi- 


irifftrriri — '""-  71 


Fig.  44. 

Urostyla  grandis.  Interference  of  galvanotaxis  and  thigmotaxis.  The 
freely  swimming  individuals  move  towards  the  cathode  (left  side). 
The  creeping  individuals  move  in  tranverse  direction. 

viduals  draw  backwards,  distribute  themselves  and  creep  and 
swim  in  all  directions  in  the  water.  If  during  the  course  of  the 
passage  of  the  current,  an  individual  which  has  been  swimming 
begins  to  creep,  the  axis  immediately  assumes  the  position  above 
described  in  the  case  of  the  organisms  which  are  in  contact  with 
the  bottom  and  vice  versa.  The  thigmotaxis,  therefore,  influences 
galvanotactically  swimming  organisms  in  a  most  characteristic 
manner.  As  a  consequence  of  the  interference  of  thigmotaxis 
and  galvanotaxis,  the  organisms  move  in  a  direction  transversely 
to  the  direction  of  the  current.  This  most  striking  reaction  has 
been  cleared  up  by  Putter,^  the  explanation  being  based  upon  an 

1  Putter:  1.   c. 


INTERFERENCE  OF  EXCITATIONS  197 

accurate  investigation  of  the  mechanism  of  cihary  activity.  The 
galvanotactic  swimming  toward  the  cathode  is  explained  by  the 
same  principle  as  that  applicable  to  all  galvanotaxis.'  As  a  result 
of  the  excitation  produced  by  the  anode,  the  cell  body  must 
assume  a  position  wherein  the  1)()rder  cilia,  whicli  are  of  greatest 
importance  in  swimming,  are  e(iually  stimulated  on  both  sides 
of  that  part  of  the  body  directed  toward  the  anode.  It  is  only 
in  this  position  that  forward  swimming  is  i)ossil)le.  for  as  a  result 
of  ^^//symmetrical  excitation  of  the  border  cilia  a  turning  must  at 
once  occur,  which  automatically  brings  al)out  a  resumi)tion  of  the 
position  of  the  long  axis.  The  perioral  cilia  bring  about  the 
screws-like  movement  around  the  axis  during  swimming.  It  fol- 
lows that  the  freely  swimming  individuals  must  necessarily  move 
towards  the  cathode.  In  the  case  of  the  thigmotactically  moving 
individuals  the  activity  of  the  border  cilia  is  inhibited.  The 
perioral  and  the  locomotion  cilia  bring  aljout  the  assumption  of 
the  position  of  the  axis,  above  described.  The  ])erioral  cilia  dur- 
ing movement  bring  about  a  turning  of  the  body  on  the  vertical 
axis  toward  the  side  opposite  that  of  the  orifice  and  it  follows 
that  the  body  can  occupy  only  that  axial  position  wherein  the 
perioral  cilia  are  least  excitated.  This  is,  however,  only  the 
case  when  the  long  axis  of  the  body  is  transverse  to  the  direction 
of  the  current,  and  the  perioral  cilia  are  directed  toward  the 
cathode,  for  stimulation  arises  from  the  anode.  The  reason  why 
the  infusoria  do  not  turn  toward  the  anode  from  this  transverse 
position  of  the  axis  is  to  be  found  in  the  fact  that  the  anterior 
locomotion  cilia  are  stimulated  to  a  greater  extent  by  the  turning 
toward  the  anode,  and  bring  about  a  movement  in  the  contrary 
direction.  The  transverse  position  of  the  axis  is  thus  the  result 
of  an  antagonistic  action  between  the  perioral  and  the  anterior 
locomotion  cilia.  It  therefore  follows  that  the  characteristic 
position,  which  is  necessarily  assumed  by  the  thigmotactically 
creeping  individuals,  is  brought  about  by  an  interference  action 
between  tactile  and  galvanic  stimulation. 

These,  then,  are  a  few  examples  of  the  interference  action  of 
various  stimuli  on  the  single  cell.     They  show  us  in  part  fairly 

\  Max   I'erworn:  "Allgemeine  Physiologic."     V  Aufl.     Jena   1909. 


198  IRRITABILITY 

simple,  and  in  part  very  complex  states.     It  now  behooves  us  to 
obtain  a  general  understanding  of  interference  action,  to  learn 
the  fundamental  lazvs  in  connection  with  these  complex  actions, 
to  shell  out,  as  it  were,  the  general  factors  involved  in  the  special 
conditions.     In  this  connection  the  examples  already  referred  to 
furnish  all  of  the  data  necessary  for  our  first  orientation.     In  the 
simple  instance  in  wdiich  the  effect  of  galvanic  stimulation  was 
augmented  by  increase  of  temperature  and  again  in  the  case  where 
there  was  a  diminution  of  excitation  resulting  from  the  alcohol, 
the    interference    of    the    two    stimuli    is    consequent    upon    the 
the  fact  that  the  location  of  attack  is  the  same.     The  constant 
current  acts  upon  a  portion  of  the  infusorium,  which  also  re- 
sponds to  elevation  of  temperature.     We  have  a  real,  or,  as  I 
may  term  it,  "homotopic  interference/'  for  it  is  an  interference 
in  which  the  general  point  of  attack  is  the  same  for  both  stimuli. 
In  contradistinction  to  this  case,  we  have  the  examples  of  the 
interference  of  thigmotaxis  and  galvanotaxis  in  the  hypotrichous 
infusoria.      Here   the   effect   of    interference,    the    characteristic 
position  of  the  axis  of  the  cell  body,  is  brought  about  by  the  fact 
that   the   galvanic   stimulus   affects   different   elements   than   the 
mechanical.     The  turning  of  a  creeping  Stylonychia  or  Urostyla, 
when  the  current  is  closed,  in  which  the  anterior  portion  of  the 
body  was  previously  directed  towards  the  anode,   results   from 
excitation  of  the  perioral  cilia  from  the  anodic  pole.     The  me- 
chanical stimulation,  on  the  contrary,  exerts  its  effect  upon  the 
locomotion  and  border  cilia.     Only  when  there  is  a  turning  of 
the  anterior  portion  of  the  body  towards  the  anode,  would  the 
galvanic   stimulus  affect  also  the  anterior  locomotion  cilia  and 
thereby  counteract  turning  towards  the  anode.     Therefore,   we 
have  before  us  in  this  case  of  the  assuming  of  a  characteristic 
position  of  the  axis  of  the  cell  body  the  expression  of  an  apparent, 
or,  as  I  prefer  to  express  it,  a  ''heterotopic  interference,"  in  which 
the  two  stimuli  do  not  actually  interfere  in  their  action,  but  rather 
influence  the  final  result,  in  that  the  condition  for  the  state  of 
the  system  in  its  totality  is  dependent  upon  its  individual  com- 
ponents.    This  heterotopic  interference  is  of  particular  impor- 
tance in  the  bringing  about  of  the  movements  of  the  living  system. 


INTKRFEREXCK  OF  KXCITATIOXS  109 

The  locomotion  of  the  animal  and  especially  the  direction  is 
in  part  a  manifestation  of  heterotoi)ic  interference  of  response. 
At  the  same  time,  however,  especially  in  the  coordinated  move- 
ments of  nervous  ori^^in,  the  h()motoi)ic  interference  also  plays 
an  important  role  and,  not  rarely,  is  combined  with  heterotopic 
interference. 

Although  the  j)hysical  analysis  of  heterotopic  interference  is 
extremely  attractive,  we  must,  however.  temi)orarily  set  aside  its 
consideration,  for  at  this  point  the  (juestion  arises  as  to  what 
happens  when  there  is  interference  of  two  stimuli  at  the  same 
point.  In  the  heterotoi)ic  interference  the  etYect  of  each  stimulus 
is  the  same  as  if  it  w^ere  applied  singly.  In  the  homotopic  inter- 
ference the  interfering  effects  of  stimulation  intUience  each  other. 

The  above  examples  of  homotopic  interference  introduce  us  to 
the  two  principal  types  of  these  manifold  kinds  of  interference 
effects;  the  excitation  brought  about  by  galvanic  stimulation  is 
summated  by  the  excitation  produced  by  temperature.  The  other 
type  consists  of  an  inhibition  of  one  effect  of  stimulation  brought 
about  by  another.  The  depression  produced  by  alcohol  on  the 
Paramecia  weakens  the  excitation  of  the  galvanic  current.  These 
examples  of  the  two  principal  types  of  interference  effects  are 
quite  simple ;  nevertheless,  in  other  cases,  the  conditions  are  very 
complex.  This  is  especially  true  in  the  field  of  nervous  inhibi- 
tion, so  important  in  the  functionation  of  the  nervous  system, 
and  wdiich  has  presented  the  greatest  difticulties  to  j^hysiological 
investigators  until  the  last  few  years.  That  a  stimulus  bringing 
about  excitation  in  a  ganglion  cell  can  l)e  inhibited  by  another 
exciting  stimulus,  or  that  the  develo])ment  of  excitation  in  a 
ganglion  cell  may  be  prevented  by  another  exciting  stimulus  can- 
not be  easily  understood.  The  ])roblem  as  to  how  two  iiUerfering 
excitations  can  bring  about  inhibition  is  one  that  has  received 
many  explanations.  An  interesting  incident  in  the  history  of 
physiology  is  that  the  first  explanation  of  the  princijiles  of  inhibi- 
tory processes  was  close  on  the  track  of  being  a  correct  one. 
but  was  subsequently  abandoned  by  its  originator.  Schiff^ 
(1858)   has  endeavored  to  explain  this  inhibition  as  a  manifes- 

1  M.  Schiff:  "r,elirl)iich  dcr   Physiologic  des  Menschen."     H.i.    I,   I.ahr    1858. 


200  IRRITABILITY 

tation  of  fatigue,  and  this  idea  he  defended  with  the  greatest 
tenacity  for  a  long  time,  until  finally,  twenty-five  years  after,  in 
a  treatise  which  he  called  "Abschied  von  der  Ershopfungstheorie," 
he  renounced  the  idea  as  untenable. 

Among  other  investigations,  which  since  this  time  have  been 
made  to  explain  the  mechanism  of  inhibition,  those  of  Gaskell,^ 
Hering-  and  Meltzer^  have  received  widest  consideration.  These 
theories  are  built  upon  the  existence  of  the  two  phases  of  metab- 
olism, and  assume  that  inhibition,  in  contradistinction  to  dissimi- 
latory  excitation  processes,  depends  upon  an  increase  of  the 
assimilative  processes.  The  principal  evidence  which  Gaskell 
advances  is  that  when  the  vagus  nerve  of  the  tortoise  heart,  a 
typical  inhibitory  nerve,  is  stimulated,  a  positive  variation  of  the 
demarcation  current  of  the  heart  muscle  occurs,  whereas  when  a 
motor  nerve  of  a  skeleton  muscle  is  stimulated  the  attached  muscle 
shows  a  negative  variation  of  the  demarcation  current.  I  must 
confess  that  this  explanation  of  inhibitory  processes,  from  the 
standpoint  of  an  interpretation  of  processes  in  the  living  sub- 
stance, seems  very  plausible,  and  I  have  accepted  this  even  in  my 
address  on  excitation  and  depression  before  the  Frankfurter 
Naturforscher  Versammlung.^  I  have  since  then  endeavored  to 
obtain  experimental  evidence  to  substantiate  this  theory,  in  that 
I  attempted  to  prove  that  increase  of  the  assimilatory  processes 
brought  about  by  stimulation  would  be  associated  with  a  reduc- 
tion of  the  specific  irritability.  For  this  purpose  I  have  sought 
for  such  cases  in  which  a  stimulus  primarily  and  momentarily 
increases  assimilative  processes  in  a  system  in  a  state  of  metabolic 
equilibrium.  I  was  disappointed,  when,  after  years  of  investiga- 
tion, I  could  not  find  such  cases.  There  is  only  one  kind  of 
stimulus  of  which  we  can  say  with  positiveness  that  it  primarily 
increases  the  assimilative  processes,  that  is,  increased  supply  of 

1  Gaskell:  "On  the  innervation  of  the  heart  with  especial  reference  to  the  heart  of 
the  tortoise."     Journ.  of  Physiology,  Vol.  IV,   1884. 

2  Ewald  Hering:  "Zur  Theorie  der  Vorgange  in  der  lebendigen  Substanz."  Lotos 
IX.  Prag  1888. 

ZMeltzer:  "Inhibition."     New  York  Medical  Journal,    1899. 

4  Max  Verworn :  "Erregung  und  Lahmung.  Vortrag  gehalten  in  der  allgemeinen 
Sitz.  der  Gesellsch."  Deutsch.  Naturf.  u.  Aerzte  zu  Frankfurt  a.  M.  1896.  Verb.  d. 
Ges.  Deutsch.  Nat.  u.  Aerzte  1896. 


INTERFERENCE  OF  EXCITATIONS  201 

food.    But  here  the  increase  in  the  processes  of  assimilation  never 
occurs    momentarily,    and    indeed    this    increase    is    so   extremely 
slight  that  it  can  only  be  demonstrated  over  a  long  course  of  time. 
These  totally  negative  results  of  my  investigation  had  awakened 
strong  doubts  concerning  the  assimilation  hypothesis  of  inhibition. 
Above  all,  this  explanation  seemed  to  me  to  be  imi)ossible  for  the 
nervous  system.     I  searched,  therefore,  for  another  explanation 
for  the  processes  of   inhibition   in   the  nervous  .system.      If  the 
increase  of  energy  production  resulting  from  the  application  of 
a   stimulus   is   dependent   upon  an  excitation   of   a   dissimilative 
nature,  then  one  is  justified  to  look  upon  the  reduction  of  func- 
tional energy  production  as  an  expression  of  an  antagonistic  pro- 
cess   to   that    of    dissimilatory   excitation.      In    this    respect    the 
G  ask  ell-He  ring  hypothesis  of  inhibition  rests  upon  a  firm  founrla- 
tion.     When,  however,  this  hypothesis  assumes  an   antagonism 
between  dissimilatory  and  assimilatory  excitation,  then   it   must 
not  be  overlooked  that  a  second  antagonism  is  possible  between 
dissimilatory  excitation  and  dissimilatory  depression.     The  antag- 
onism  need   not   involve   the  two  types   of   metabolism,    it   may 
depend  upon  variations  of  one  type.     When,  therefore,  the  hy- 
pothesis that  inhibition  is  brought  about  by  assimilatory  excita- 
tion meets  with  insuperable  difficulties,  the  possibility  should  be 
considered  if  it  is  not  more  likely  dependent  upon  dissimilatory 
depression.     These  reflections  induced  me  to  investigate  if  con- 
ditions could  not  be  produced  experimentally  wherein  dissimi- 
latory depression  could  bring  about  inhibitory  processes  in  the 
nervous  system.     The  most  essential  requirement  was,  that  dis- 
similatory depression  should  quickly  develop  and  pass  away  witli 
like  rapidity,  for  inhibition  of  the  nervous  system  sets  in  momen- 
tarily  and    disappears    again   momentarily.      Another    important 
requisite  is,  that  both  interference  stimuli  arc  individually  capable 
of  producing  dissimilatory  excitation,  for  the  inhibitory  processes 
of  the  nervous  type  may  be  assumed  to  be  the  result  of  dissimi- 
latory excitation  which  j)ro(luce  by  their  interference  inhibition, 
for  the  nerve  fibers,  as  already  stated,  are  capable  of  c(Miducting 
only    dissimilatory   excitation   to   the    responding   organ.      As    I 
studied  the  problem  in  this  manner,  it  became  clear  to  mc  that  all 


202 


IRRITABILITY 


the  conditions  necessary  for  the  genesis  of  inhibition  are  realized 
in  the  existence  of  the  refractory  period,  and  that  I  had  already 
produced  inhibition  by  prolonging  the  refractory  period,  by 
oxygen  withdrawal,  in  the  strychninized  frog.  If  we  take  a 
strychninized  frog  in  which  the  refractory  period  has  been  some- 
what prolonged  by  oxygen  withdrawal,  so  that  the  reaction  is 
simply  a  short  reflex  contraction,  and  rhythmically  stimulate  the 
skin,  a  reaction  is  only  obtained  with  the  first  few  stimuli,  which 


Fig.  45. 
Lower  line  indicates  stimuli. 


reactions  rapidly  decrease  until  a  stage  is  reached  wherein  the 
succeeding  stimuli  are  completely  inoperative.  (Figure  45.)^ 
This  inhibition  is  demonstrated  even  more  clearly  by  the  following 
experiment.  Contractions  of  the  triceps  muscle  of  a  strychninized 
frog  are  recorded  which  reflexly  follow  from  stimulation  of  the 

1  Max  Verworn:  "Zur  Kenntniss  der  physiologischen  Wirkungen  des  Strychnins." 
Arch.  f.  Anat.  u.  Physiol,  physiolog.  Abth.  1900.  The  same:  "Ermiidung,  Erschopfung 
und  Erbolung."     Ibidem  Suppl.    1900. 


INTERFERENCE  OF  EXCITATION'S 


203 


central  end  of  the  cut  sciatic  nerve.  Oxygen  is  witlidrawn  in  the 
manner  already  referred  to.  At  the  ])ro])cr  stage  of  oxygen 
deficiency,  rhythmic  induction  shocks  ai)i)licd  to  the  central  end 
of  the  nerve,  the  interval  between  the  individual  stimuli  of  which 
being  longer  than  the  duration  of  the  refractory  period,  elicit 
reflex  contractions  of  the  nuiscles  of  the  posterior  extremity  on 
the  opposite  side  following  each  individual  stimulus.  If,  how- 
ever, in  the  same  stage  the  central  end  of  the  nerve  is  stimulated 
with  induction  shocks  at  intervals  briefer  than  the  duration  of 
the  refractory  period,  a  contraction  is  only  observed  during  the 


Fig.  46. 

Reflex  inhibition  in  the  strychninized  frog.  Lx)wer  line  indicates  seconds,  upper  line  stimuli. 
When  stimulation  with  single  shocks  at  longer  intervals  is  applied,  each  sinjjie  stimu- 
lus is  effective.  When  faradic  stimulation  is  used,  only  the  first  stimulus  is  operative, 
and  during  the  further  continuance  of  stimulation  inhibition  takes  place  in  the  spinal 
cord. 


very  beginning,  being  brought  about  by  the  first  stimulus,  whereas 
the  subsequent  stimuli  are  ineffective,  the  nuiscles  remaining  at 
rest  during  their  entire  application.  (Figure  46.)  Ticdcmanu^ 
at  a  later  date  continued  these  observations  and  analyzed  them 
more  in  detail.  In  all  these  experiments,  therefore,  there  is  an 
interference  of  the  frequent  stimulus,  because  each  succeeding 
stimulus  occurs  in  the  refractory  period  of  the  ]iroceeding.     In 

1  Tiedemann:  "Untersuchungen  iiber  das  absolute  Rcfractarstadium  und  die 
Hemmungsvorgange  im  Riickcnmark  des  Strychninfroschcs."  Zeitschr.  f.  allgcm. 
Physiologic   Bd.   X,   1910. 


204  IRRITABILITY 

consequence  there  is  a  strong  reduction  of  irritability  and  re- 
action is  absent.  That  is,  the  centers  during  appHcation  of  the 
frequent  current  are  inhibited.  If  cessation  of  stimulation  by 
frequent  shocks  takes  place,  stimulation  by  slowly  succeeding 
individual  shocks  becomes  effective  again  in  a  few  seconds.  This 
is  the  simplest  example  of  the  process  of  inhibition  and  by  it  I 
was  led  to  seek  in  the  refractory  period  the  key  of  the  mechan- 
isms of  the  process  of  inhibition.  This  principle  once  recognized, 
further  material  for  the  more  detailed  working  out  and  extension 
of  the  theory  was  gathered  from  the  experiences  already  gained 
during  the  course  of  the  preceding  years  in  the  researches  on 
fatigue  and  the  refractory  period  in  the  nerve.  Here  it  became 
apparent  that  the  processes  resembling  inhibition  discovered  by 
Schiff  in  the  nerve  preparation  and  which  were  studied  anew  at 
a  later  date  by  Wedenski,  F.  B.  Hofmann  and  Amaja  and  in  part 
attributed  by  Hofmann  to  fatigue  of  the  nerve  endings,  by 
Frohlich  to  fatigue  of  the  nerve  itself,  were  in  principle  of  the 
same  nature  as  the  central  inhibitions  themselves.  Frohlich,^  by 
his  analysis  of  the  observations  of  Richet,  Liichsinger,  Fick, 
Biedermann  and  Piotrowski  on  inhibition  in  the  claw  of  the  crab, 
then  showed  that  inhibition  can  be  influenced  by  the  alteration  of 
the  intensity  of  the  stimulus  as  well  as  its  frequency.  In  a  series 
of  experimental  researches  he  could  then  demonstrate  that  the 
widely  extended  antagonistic  inhibitions  and  other  special  pro- 
cesses of  inhibitions  in  the  centers  could  on  the  basis  of  the  same 
principle  be  physiologically  explained.  Here  the  supposition  was 
confirmed  that  the  development  of  a  relative  refractory  period 
plays  a  very  important  role  in  the  inhibition  of  the  nervous  cen- 
ters. Thus,  the  relations  of  the  processes  of  inhibition  to  the 
refractory  period,  once  established,  their  entire  field,  up  to  then 

\  Fr.  W.  Frohlich:  "Die  Analyse  der  an  der  Krebsschere  auftretenden  Hemmun- 
gen."  Zeitschr.  f.  allgem.  Physiologie  Bd.  VII,  1907.  The  same:  "Der  Mechanismus 
der  nervosen  Hemmungsvorgange."  Medizin.  naturwiss.  Arch.  Bd.  I,  1907.  The 
same:  "Beitrage  zur  Analyse  der  Reflexf unction  des  Riickenmarks  mit  besonderer 
Berucksichtigung  von  Tonus,  Bahnung  und  Hemmung."  Zeitschr.  f.  allgem. 
Physiologie  Bd.  IX,  1909.  The  same:  "Experimentelle  Studien  am  Nervensystem  der 
Mollusken  12.  Summation  und  scheinbane  Bahnvuig,  Tonus,  Hemmung  und 
Rhythmus  am  Nervensystem  von  Aplysia  limacina."  Zeitschr.  f.  allgem.  Physiol.  Bd. 
XI,    1910. 


INTERFERENCE  OF  EXCITATIONS  205 

shrouded  in  darkness,  has  gradually  in  the  course  of  years  been 
completely  elucidated. 

Before  going  back  to  the  cases  of  inhibition  and  explaining 
them  by  this  general  principle,  it  is  necessary  tiiat  we  penetrate 
more  deeply  into  the  details  of  the  characteristic  course  of  the 
refractory  period.  ]*>y  this  means  we  will  tind  tiie  conditions 
which  universally  determijie  the  interference  in  the  efTccts  of 
stimulation. 

First  of  all,  it  is  self-evident  that  the  occurrence  of  interference 
of  stimulation  in  a  living  system  can  only  take  i)lace  when  the 
succeeding  stimulus  is  ai)plied  before  the  etTects  of  the  previous 
one  have  completely  disappeared.  Within  the  interval,  however, 
which  is  involved  from  the  moment  of  the  beginning  of  a  stimulus 
until  its  effect  disappears  through  the  self -regulation  of  metal)- 
olism,  there  is  the  possibility  of  various  interference  results  from 
stimulation. 

If  we  take  into  consideration  the  various  instances  which  can 
arise,  perhaps  we  may  best  start  with  that  tyi)e  wherein  the  first 
stimulation  produces  depression,  whereas  the  second  has  an  excit- 
ing effect  on  disintegration.  In  this  type  the  response  to  the 
second  stimulus  is  weaker  than  when  the  second  stimulus  alone 
is  applied.  As  a  concrete  example  of  this  type,  we  may  refer  to 
the  interference  of  an  induction  shock  in  a  nerve  during  the 
relative  want  of  oxygen.  We  arrange  a  nerve  of  a  nerve  muscle 
preparation  of  a  frog  in  a  glass  chamber,  as  already  described,  and 
determine  the  threshold  of  stimulation  of  the  stretch  within  the 
chamber  by  the  weakest  induction  shocks  which  produce  response. 
The  oxygen  is  then  removed  and  the  eft'ect  on  the  threshold  de- 
termined. As  shown  by  Baeycr  it  is  found  that  with  increasing 
asphyxia  the  threshold  of  stimulation  for  induction  shocks  be- 
comes continually  higher.  The  irritability  is  likewise  decreased. 
This  occurs,  as  the  investigations  of  Lodholz  show,  at  first  slowly, 
then  more  and  more  rapidly.  The  curve  of  the  decrease  of  irri- 
tability has  a  logarithmic  form.  During  the  continuation  of  the 
depressing  stimulus,  i.e.,  the  want  of  oxygen,  the  exciting  stimulus 
has  less  and  less  eft"ect.  If  oxygen  is  again  brought  in  contact 
with   the   nerve,   irritability   immediately   returns   to   its   original 


206  IRRITABILITY 

height.  The  cessation  of  the  depressing  stimulus  has,  therefore, 
the  effect  that  the  exciting  stimulus  again  brings  about  its  original 
response. 

A  second  type  of  interference  is  produced  when  both  stimuli 
bring  about  depression.  As  an  example,  we  may  select  the  inter- 
ference of  cold  and  deficiency  of  oxygen.  If  we  assume,  for 
instance,  that  each  of  these  stimuli  of  itself  brings  about  only  a 
partial  reduction  of  liVing  processes  and  not  a  complete  suppres- 
sion, then  it  would  be  possible  to  think  of  a  summation  of  both 
depressions.  Nevertheless,  the  conditions  for  the  summation  of 
depression  have  never  been  carefully  analyzed.  Quantitative 
investigations  upon  the  interference  of  depressing  stimuli  are 
entirely  lacking.  One  should  not,  however,  in  physiology  pre- 
suppose what  may  happen  under  certain  given  conditions  with- 
out first  making  the  necessary  experiments.  The  strength  of 
scientific  investigation  depends  upon  the  fact  that  every  deduc- 
tion, no  matter  how  small,  must  be  substantiated  by  experience 
before  further  progress  can  be  made.  So,  likewise,  we  must 
await  the  results  of  thorough  experimentation  upon  the  inter- 
ference of  depressing  stimuli  before  we  can  establish  a  law.  The 
conditions  are  not  as  simple  as  they  appear  on  first  observation, 
for  the  point  of  attack  of  the  various  kinds  of  the  depressing 
stimuli  upon  the  chain  of  metabolic  processes  may  be  very  differ- 
ent. In  such  a  case  it  is  not  at  once  possible  to  understand  the 
results  of  the  interference. 

There  is  a  third  type  in  which  two  dissimilatory  excitations 
interfere  with  each  other.  Fortunately  there  is  a  great  amount 
of  experimental  data  at  our  command  so  that  today  we  have  a 
clear  understanding  of  the  essential  points  of  the  conditions 
necessary  for  the  development  of  summation  of  excitation  on  the 
one  hand,  and  inhibition  on  the  other.  If  we  take  an  instance 
of  a  momentary  dissimilatory  excitation  operating  upon  an 
aerobic  system  in  metabolic  equilibrium,  it  is  necessary  to  recall 
the  two  effects  thereby  produced.  The  stimulus  brings  about  an 
oxydative  decomposition  of  the  living  substance.  Likewise  there 
is  a  reduction  of  irritability.  Both  of  these  alterations  are  the 
foundation  of  interference.     Both  processes  have  a  specific  time 


INTERFERENCE  OF  EXCITATIONS 


207 


of  occurrence.  The  disintegration,  determined  by  energy  pro- 
duction, reaches  a  maximum  suddenly,  then  diminishes,  at  tirst 
rapidly,  then  more  and  more  slowly  until  the  zero  point  is  reached. 
In  an  analogous  manner  the  irritability  abruj)tly  reaches  a  mini- 
mum, then  increases  rai)i(lly,  then  more  slowly,  until  it  again 
reaches  its  previous  value.  When  we  represent  these  processes 
by  a  curve,  they  assume  the  following  form.     (Figure  47.)     In 


Fig.  47. 


this  diagram  the  abscissa  is  the  time,  the  ordinate  value  zero  is 
the  level  of  the  metabolism  of  rest  and  the  specific  irritability. 
The  points  above  the  abscissa  represent  disintegration,  that  is, 
energy  production,  those  under  the  abscissa,  the  reduction  of  irri- 
tability. A  consideration  of  the  latent  period  may  be  omitted. 
At  the  end  of  the  curve  the  effect  of  stimulation  may  be  assumed 
to  have  disappeared  and  the  state  of  metabolic  cciuilibrium  re- 
established. If  we  base  our  further  observations  upon  this  curve 
of  excitation,  we  can  study  in  them  the  factors  upon  which 
responsivity  is  dependent  when  a  second  exciting  stinuilus  is 
operative  during  the  course  of  the  first. 

It  is  from  the  beginning  apparent  that  the  resix)nse  to  the 
second  stimulus  is  determined  by  the  intensity  of  the  second 
stimulus  in  relation  to  the  degree  of  irritability  which  exists  at 
the  moment  when  this  is  effective.  This  relation  is  dependent 
first  upon  the  absolute  intensity  of  the  second  stinuilus.  In  the 
following  diagram  the  intensity  of  the  existing  threshold  value  is 


208 


IRRITABILITY 


fixed  for  convenience  as  ordinates  beneath  the  abscissa.  If,  for 
example,  at  the  time  point  x,  a  stimulus  of  weak  intensity  Ri  acts, 
this  stimulus  being  under  the  existing  threshold,  produces  no 
perceptible  effect.  (Figure  48.)  If  now  instead  of  a  weak  stimu- 
lus, one  of  stronger  intensity  acts  at  the  time  point  x,  this  stimulus 


Fig.  48. 


Fig.  49. 


will  produce  an  appreciable  response.  (Figure  49.)  If  the  sec- 
ond stimulus  is  of  the  same  strength  as  the  first,  this  second  stimu- 
lus will  bring  about  relatively  less  disintegration,  because  the 
system  is  then  in  a  state  in  which  irritability  is  still  reduced. 
But  this  lessened  disintegration  in  that  it  summates  the  excita- 
tion still  existing  as  the  result  of  the  first  stimulus  can  produce 
an  absolute  increase  of  the  height  above  that  of  the  abscissa. 


INTERFERENCE  OF  EXCITATIONS 


209 


Here  then  we  see  the  possibiHty  of  an  increase  of  response 
resulting  from  summation.  Accorthngly  the  increase  of  disin- 
tegration must  occur  simultaneously  with  a  diminution  of  irri- 
tability and  this  must  fall  below  the  level  of  the  reduction  of 
irritability  produced  by  the  first  stimulus.  This  augmentation  of 
the  response  through  summation  above  the  level  of  that  i)ro- 
duced  by  the  first  stimulus  acting  ujjon  an  unexcitatcd  system  is, 
however,  connected  with  another  condition.  The  above  e.\ami)le 
refers  to  systems  in  whicli  weak  stinuili  bring  about  weak  re- 
sponse and  strong  stimuli  .strong  response,  that  is.  the  resj^onse 
is  capable  of   increase.      In   systems  in   which   the   "all   or  none 


Fig.  50. 


law"  is  applicable,  such  an  alteration  in  the  absolute  height  of 
excitation,  as  results  in  summation,  is  not  possible.  In  order  to 
characterize  these  two  types  of  living  systems  by  a  short  exi)res- 
sion  rather  than  by  a  long  sentence,  we  will  call  the  first  a 
''heteroholic  system,"  the  latter  in  which  the  "all  or  none  law"  is 
operative  an  "isobolic  systc)}i."  The  former  term  expresses 
various  degrees  of  discharge  dei)ending  upon  the  intensity  of  the 
stimulus,  the  latter  term  refers  to  the  constancy  of  discharge 
following  stimuli  of  various  intensities.  Isobolic  systems  are  in 
contradistinction  to  the  heterobolic  systems  not  cai)able  of  summa- 
tion. The  response  to  the  second  stimulus  of  e(|ual  intensity 
cannot  be  greater  than  that  of  the  first,  it  may  be  ecjual  to  the 
first  (Figure  50)  or  be  less  in  extent,  but  it  can  never  be  greater 


210 


IRRITABILITY 


than  that  resulting  when  a  single  stimulus  is  applied.  These  facts 
have  been  known  for  a  long  time  in  the  case  of  the  heart  muscle. 
A  word  is  necessary,  however,  concerning  the  effect  of  stimuli 
beneath  the  threshold  in  heterobolic  systems.  We  must  here 
distinguish  between  the  ''ideal"  threshold,  beneath  which  the 
influence  of  a  stimulus  is  nil,  and  the  threshold  of  perceptible 
effect,  beneath  which  a  stimulus  apparently  has  no  effect;  never- 
theless a  weak  eft'ect  does  occur,  as  is  shown  by  succeeding  re- 
actions. This  effect  is  manifested  by  a  sub-threshold  disinte- 
gration and  a  corresponding  slight  reduction  of  irritability. 
(Figure  51.)       The  presence  of  such  a  sub-threshold  effect  is 


Fig.  51. 

Effect  of  sub-threshold  stimuli,    o— Level  of  the  ideal  threshold, 
s— Level  of  the  threshold  of  perceptible  effect. 


recognized  by  various  facts  as,  for  example,  the  summation  of  the 
sub-threshold  stimuli  to  production  of  a  perceptible  result.  Thus 
stimulation  of  a  sensory  spinal  cord  root  with  a  single  sub- 
threshold induction  shock  will  not  produce  any  evidence  of  a 
reflex  excitation,  whereas,  when  induction  shocks  of  the  same 
strength  and  of  sufficient  frequency  are  applied,  a  strong  reflex 
contraction  results.  The  fact  that  sub-threshold  stimuli  can  bring 
about  sub-threshold  effects  is  also  important  in  consideration  of 
the  result  of  interference.  The  relation  between  the  intensity  of 
the  second  stimulus  and  the  degree  of  irritability  of  the  system, 
the  intensity  of  the  stimulus  being  absolutely  constant,  depends, 


LNTERFERENCE  OF  EXCITATIOXS 


211 


secondly,  upon  the  momentary  amuunt  of  irritability  which  exists 
just  at  the  time  when  the  second  stimulus  produces  its  effects. 
It  is,  therefore,  clear  that  the  response  produced  hy  interference 
must  also  alter  with  the  momentary  deforce  of  irritability  in  a 
manner  analogous  with  variations  of  the  intensity  of  the  second 
stimulus.  One  nuist,  therefore,  know  the  factors  which  control 
the  momentary  degree  of  excitation. 

The  first  factor  to  be  considered  is  the  moment  of  time  in  which 
the  second  stimulus  is  ai)plied,  that  is,  the  interval  between  the 
first  and  the  second  stimulus.  If,  for  example,  a  weak  second 
stimulus  follows  very  cjuickly  after  the  first,  the  stimulus  will 
bring  about  no  response,  as  the  system  at  the  time  of  its  appli- 
cation is  in  a  relative  refractory  period.  (Figure  IS.)  The 
stimulus  is,  therefore,  under  the  threshold,  [f,  however,  a  stinui- 
lus  of  the  same  strength  is  applied  somewhat  later,  when  the  irri- 
tability has  already  increased  to  a  somewhat  greater  extent,  then 
at  this  moment  the  stimulus  is  above  that  of  the  threshold  and 
a  response  is  obtained  which,  on  account  of  the  state  of  irritability 


Fig.  52. 


existing,  is  summated.  (Figure  52.)  But  further,  ii  is  not  a 
question  of  the  absolute  interval  between  the  stimuli.  I)ut  rather 
to  the  relative  interval  to  the  specific  rapidity  of  the  reaction  of 
the  living  substance  under  consideration.  There  arc  living  sub- 
stances, as  we  have  seen,  in  which  the  refractory  perio<l  is  un- 
usually short,  as,  for  instance,  the  nerve.      There  are  other  sub- 


212  IRRITABILITY 

stances  wherein  this  period  lasts  a  considerable  time  after  stimu- 
lation, that  is,  before  the  irritability  returns  to  the  original  level, 
as,  for  example,  the  smooth  muscle.  Indeed,  depending  upon 
the  specific  properties  of  a  system,  a  short  or  a  long  interval  is 
required  before  a  stimulus  of  a  given  intensity  is  again  operative. 
Finally,  in  one  and  the  same  living  system  the  duration  of  the 
refractory  period  can  be  very  different,  depending  upon  the 
momentary  state  of  the  system.  Above  all  we  know  that  the 
refractory  period  is  considerably  prolonged  in  fatigue  and  like- 
wise after  the  influence  of  other  agents,  as  narcotics,  lowering  of 
the  temperature,  etc.  In  such  states  a  second  stimulus  remains 
inoperative  when  it  follows  at  a  definite  interval  from  the  first, 
whereas  under  normal  conditions  the  same  stimulus  applied  at  the 
same  interval  would  be  operative. 

Finally,  there  is  another  factor  to  be  considered,  namely,  that 
the  latent  period  of  the  second  stimulus  is  more  and  more  pro- 
longed as  the  second  stimulus  approaches  more  closely  to  the 
absolute  refractory  period  of  the  first.  In  the  above  schemes  the 
latent  period  was  not  taken  into  consideration  because  practically 
for  all  the  intervals  of  stimulation  considered  at  that  time  it  could 
be  assumed  to  be  the  same.  When,  however,  a  decrease  of  the 
intervals  between  the  individual  stimuli  takes  place,  the  prolonga- 
tion of  the  latent  period  can  then  not  be  overlooked,  as  it  leads  to 
a  retardation  of  response.  (Figures  29,  30.)  This  fact  was  shown 
in  the  classic  investigations  of  Marey^  upon  the  refractory  period 
of  the  heart,  and  more  recently  has  been  the  subject  of  study 
by  Samojloff,^  Keith  Lucas^  and  Gotch^  in  the  muscle  and 
nerve.  These,  then,  are  the  essential  factors  which  bring  about 
interference,  and  although  there  are  special  details  which  deserve 

1  Marey :  "Des  excitations  artificielles  du  coeur."  Trav.  du  lab.  de  M.  Marey  II, 
1875.  The  same:  "Des  mouvements  que  produit  le  coeur  lorsqu'il  est  soumis  a  des 
excitations  artificielles."     Compt.  rend,  de  I'acad.   des  sciences  T.    LXXXVII,   1876. 

2  Samojloff :  "Actionsstrome  bei  summierten  Muskelzuckungen."  Arch.  f.  Physio- 
logic Suppl.  1908.  The  same:  "Uber  die  Actionsstromkurve  des  quergestreiften 
Muskels  bei  zwei  rasch  aufeinanderfolgenden  Reizen."     Zentralblatt  f.  Physiol.   1910. 

3  Keith  Lucas:  "On  the  refractory  period  of  muscle  and  nerve."  Journ.  of  Physiol- 
ogy, XXXIX,  1909-10.  The  same:  "On  the  recovery  of  muscle  and  nerve  after  the 
passage  of  a  propagated  disturbance."     Ibid.   XXXXI,   1910-11. 

4Gotch:  "The  delay  of  the  electrical  response  of  nerve  to  a  second  stimulus." 
Journ.    of   Physiology,    XXXX,    1910. 


INTERFERENCE  OF  EXCITATIONS 


213 


more  close  analysis,  nevertheless,  we  are  in  a  position  to  attribute 
to  them  the  origins  of  summation  and  inhibitory  processes,  wliich 
occur  in  all  living  systems,  especially  the  nervous  system. 

For  the  analysis  of  summation  and  the  inhibitory  processes 
which  occur  in  the  i)hysiologically  active  organisms  or  wiiich  are 
experimentally  produced,  a  very  imi)ortant  point  should  be  ob- 
served, that  is,  the  fact  that  the  stimuli  which  bring  about  these 
phenomena  are  practically  always  a  scries  of  single  stimuli.  The 
nerve  impulses,  for  example,  consist  of  a  shorter  or  a  longer 
series  of  single  discharges  which  follow  each  other  in  raj)i(l 
rhythmic  sequence.  Here,  then,  we  have  the  conditions  neces- 
sary for  the  production  of  interference  effects  when  these  single 
stimuli  follow  each  other  with  sufficient  frequency  and  also  when 
there  is  the  combined  action  of  huo  series. 


\ 

/ 

(  / 

[     / 

\      J 

,,-'"' 

,^-"' 

-■-",. 

' 

T--; 

--;■;;.■. 

■....-• 

V 

/ 

w 

\  r 

\  / 

\  } 

\  / 

\  / 

V  / 

\  / 

\  / 

•s-'      / 

\'     /■ 

V     / 

»^     / 

V     /- 

;  >^ 

Fig.  53. 

Curve  showing  the  general  development  of  the  effect  produced  by  interference  of  the 
stimuli  of  the  same  series  in  an  heterobolic  system.  The  effect  is  first  summation 
and  then  inhibition.  R  indicates  the  intensity  of  the  stimuli.  S  the  level  of  the 
threshold  of  perceptible  effect. 


We  wdll  first  direct  our  attention  to  the  simi)lest  case  brought 
about  by  an  interference  between  the  individual  effects  of  stimuli 
in  the  same  series.  \\'e  will  study  the  effect,  which  here  occurs, 
in  the  accompanying  diagram,  which  shows  the  facts  involved  in 
the  interference  of  tzvo  stimuli  of  a  scries  of  stimuli.  (  h'igure 
53.)  The  curve  shows  the  development  of  summation  and  inhi- 
bition. The  single  stimuli  of  equal  intensity  follow  at  the  same 
intervals,  so  that  the  succeeding  stimuli  meet  with  an  incomplete 


214  IRRITABILITY 

recovery  of  excitation  and  accordingly  a  decreased  state  of  irri- 
tability. In  spite  of  the  diminution  of  the  relative  response  to 
each  stimulus  the  summation  of  excitation  brings  about  an 
absolute  increase  of  the  same.  At  the  same  time  the  irritability 
decreases  more  and  more,  for  after  each  stimulation  the  oxydative 
disintegration  as  well  as  restitution  require  a  progressively  greater 
time  and  a  relative  fatigue  must,  therefore,  necessarily  develop. 
The  summation,  consequently,  reaches  its  limit  very  soon  and 
then  decreases  progressively,  for,  as  a  result  of  the  increase  of 
fatigue,  the  oxydative  decomposition  which  occurs  at  the  instant 
of  every  stimulation  reduces  and  with  this  the  energy  production 
becomes  less  and  less.  The  system  is  relatively  refractory  for 
the  given  intensity  of  stimulus.  Accordingly  the  response  to  stim- 
ulation falls  below  the  threshold  of  perceptible  response  (dotted 
line  S)  and  finally  an  equilibrium  between  disintegration  and 
restitution  occurs,  wherein  the  small  amount  of  material  used  at 
each  stimulation  by  oxydative  decomposition  is  again  replaced 
before  the  next  stimulus.  In  other  words,  the  irritability  is  re- 
duced at  each  stimulation  to  an  amount  equal  to  that  of  the 
recovery  in  the  interval.  If  this  all  takes  place  beneath  the  thresh- 
old of  perceptible  response,  the  system  during  the  contin- 
uance of  the  stimulation  seems  responseless,  that  is,  inhibited. 
The  inhibition  consists  then  of  a  reduction  of  irritability  below 
the  perceptible  threshold  of  response  of  the  stimulus  concerned. 
It  depends  upon  a  continued  lessening  of  dissimilative  excitation 
to  a  low  level  through  the  delay  of  the  oxydative  decomposition 
processes.  The  inhibition  is  according  to  this  a  relative  fatigue, 
which  is  conditioned,  as  is  true  of  every  fatigue,  by  a  lengthening 
of  the  refractory  period  following  a  relative  deficiency  of  oxygen. 
The  processes  of  inhibition  are  simply  and  solely  an  expression 
of  a  refractory  period  persisting  as  a  result  of  dissimilatory 
excitating  stimuli. 

Accordingly  the  general  conditions  requisite  for  summation 
on  the  one  side  and  inhibition  on  the  other  may  be  formulated 
as  follows : 

A  summation  may  develop  in  a  heterobolic  system  and  by  the 
use  of  submaximal  stimuli.     It  always  develops  when  the  follow- 


INTERFERENCE  OF  EXCITATION'S  215 

ing  stimulus  is  applied  before  there  is  complete  recovery  of  exci- 
tation from  the  previous  stimulus.  The  absolute  increase  of 
excitation  as  a  result  of  summation  is,  however,  limited  by  the 
diminution  of  irritability.  Hy  continuation  of  the  series  of  stimuli 
the  state  of  ecjuilibrium  between  the  amount  of  excitation  and 
the  irritability  will  be  established  on  a  hi^dicr  or  hnver  level. 
There  occurs  then,  depending  on  whether  the  feeble  persistent 
excitation  remains  above  or  below  the  level  of  perceptible  effect, 
either  a  tonus  or  an  inhibition. 

Summation  can  be  transformed  into  inhibiticjn  by  the  continu- 
ance of  stimuli  of  constant  intensity.  The  i)rinciples  which  under- 
lie both  processes  are  in  no  way  antagonistic  and  indeed  are  not 
separated  by  distinct  boundaries.  The  diagram  here  shown 
(Figure  53)  illustrates  this  development  of  summation  and  inhi- 
bition. The  time  required  for  this  development  is  in  manifold 
ways  influenced  by  variations  of  the  above-stated  factors  which 
control  the  occurrence  of  interference.  There) )y  results  an 
immense  number  of  special  cases  which  differentiate  themselves 
in  characteristic  manner  depending  on  whether  an  isobolic  or 
heterobolic  system  is  involved,  depending  on  whether  the  irri- 
tability of  the  system,  as  measured  by  the  threshold  of  stimula- 
tion, is  high  or  low,  depending  on  whether  fatigability  is  great  or 
small,  depending  upon  the  intensity  and  frequency  of  the  stimuli, 
etc.  Analysis  of  every  instance  shows  us  different  combinations 
of  the  interaction  of  the  individual  factors.  It  is,  therefore,  self- 
evident  that  we  cannot  here  analyze  a  greater  number  of  these 
cases  of  summation  and  inhibition.  I  wish  only  to  refer  to  a  few 
typical  examples  at  this  time. 

It  is  known  that  summation  of  excitation  in  the  normal  nerve 
does  not  occur.  As  already  stated,  the  nerve  is  a  system  in  which 
the  "all  or  none  law"  is  operative,  v^uch  isobolic  systems  do  not 
summate,  having  no  power  of  summation  because  each  individual 
stimulus  brings  about  a  maximum  response.  lUit  we  have  seen 
that  the  nerve,  as  a  result  of  depressing  factors,  such  as  deficiency 
of  oxygen,  narcosis,  fatigue,  etc..  which  decrease  its  irritability, 
can  be  transformed  from  an  isobolic  into  a  heterobolic  system. 
In    this    state    the    nerve    possesses    the    capal)ilily    of    summat- 


216  IRRITABILITY 

ing  excitations.  Waller,^  Boruttau,-  Boruttan  and  Frohlich,^ 
Thorner^  and  others  have  shown  that  the  action  current  of  the 
nerve  during  the  appHcation  of  tetanic  stimulation  becomes  decid- 
edly greater  during  a  certain  stage  of  narcosis  or  asphyxiation, 
so  that  the  wave  of  negative  variation  is  higher  than  when  the 
nerve  is  excitated  by  a  single  induction  shock.  Frohlich^  first 
threw  light  upon  this  subject  in  that  he  made  the  observation 
that  here  a  principle  is  involved  which  has  far-reaching  impor- 
tance in  the  phenomena  occurring  in  the  organism.  He  showed 
that  as  a  result  of  fatigue,  cold  and  narcosis,  etc.,  the  course  of 
excitation  brought  about  by  the  single  stimulation  undergoes 
retardation.  These  conditions  within  certain  limits  become  more 
favorable  for  the  production  of  summation,  because  each  succeed- 
ing stimulus  meets  with  a  more  incomplete  recovery  of  excitation 
than  the  one  previously  applied.  In  consequence  of  this,  the  irri- 
tability of  the  system  in  the  beginning  of  fatigue,  or  narcosis,  or 
immediately  after  the  application  of  cold,  is  apparently  increased. 
This  ''apparent  excitation,"  as  it  was  called  by  Frohlich,  depends, 
however,  in  reality  upon  a  beginning  depression  which  is  evident 
in  that  the  course  of  the  individual  excitations  are  lengthened  by 
this  means.  The  irritability  is  likewise  also  reduced.  Reinecke^ 
later  studied  in  further  detail  the  retardation  of  excitation  in  the 
muscle  and  attributed  to  this  the  characteristic  property  shown 
in  muscle  in  the  so-called  "reaction  of  degeneration."  Fatigue, 
asphyxia,  cold,  degeneration,  in  fact  all  factors  which  retard  the 

1  Waller:  "Observations  on  isolated  nerve."  Croonian  Lecture,  Philosophical 
transactions.      1897. 

2  Boruttau:  "Die  Actionsstrome  und  die  Theorie  der  Nervenleitung."  Pfliigers  Arch. 
Bd.   84,    1901. 

3  Boruttau  und  Frohlich:  "Electropathologische  Untersuchungen.  Ueber  die 
Aenderung  der  Erregungswelle  durch  Schadigung  des  Nerven."  Pflugers  Arch.  Bd. 
105,    1904. 

4  Thorner:  "Die  Ermijdung  des  markhaltigen  Nerven."  Zeitschr.  f.  allgem.  Physi- 
ologic Bd.  VIII,  1908,  und  Bd.  X,  1910. 

5  Fr.  IV.  Frohlich :  "Ueber  die  scheinbare  Steigerung  der  Leistungsfahigkeit  des 
quergestreiften  Muskels  im  Beginn  der  Ermiidung  (Muskeltreppe),  der  Kohlensaure- 
wirkung  und  Wirkung  anderer  Narkotica  (Aether,  Alkohol)."  Zeitschr.  f.  allgem. 
Physiologie  Bd.  V,  1905.  The  same:  "Das  Princip  der  scheinbaren  Erregbarkeits- 
steigerung."      Zeitschr.    f.   allgem.   Physiologie   Bd.    IX,    1909. 

6  Fr.  Reinecke:  "Ueber  die  Entartungsreaction  und  eine  Reihe  mit  ihr  verwandter 
Reactionen."     Zeitschr.   f.   allgem.  Physiologie  Bd.   VIII,   1908. 


INTERFERENCE  OF  EXCFrXTK  )XS 


2ir 


course  of  excitation,  are  favorable  to  the  summation  of  excitation, 
provided  their  iiitluence  does  not  exceed  certain  limits. 

Although  the  nerve  as  an  isoholic  system  can  only  he  rendered 
capable  of  exhibiting  summation  when  artificially  influenced, 
there  are  other  forms  of  li\ing  substance  which  normally  are 
systems  with  a  slow  course  (jf  excitation,  in  which  excitation 
may  be  summated,  for  this  type  possesses  at  the  same  time  a 
heterobolic  character.  Vuv  example,  a  single  mechanical  exci- 
tation elicits  a  hardly  perceptible  response  in  Amivba,  Actino- 
splucrium,  Orbitolitcs.  When  it  is  perce])til)le  at  all,  there  occurs 
a  short  interruption  of  the  centrifugal  uKJvement  of  the  proto- 
plasm. After  a  i)ause  the  movement  of  the  ])rotoj)lasm  and  the 
stretching  out  of  the  pseudopods  again  return.  Ihu  if  the 
organism  is  agitated  one  or  more  minutes  by  rhythmically  shak- 
ing the  edge  of  the  slide  by  a  special  device,  as  a  result  of  the 
summation  of  weak  excitations  there  occurs  a  comi)lete  drawing 
in  of  the  pseudopods  and  the  anKcbre  become  bell-shajied.'  The 
ganglion  cells  also  possess  a  great  cai)ability  for  summation.  W'e 
have  already  alluded  to  the  fact  that  single  induction  shocks 
below  that  of  the  threshold  produce  no  evident  effect,  whereas 
when  rapidly  repeated,  summation  occurs  with  reflex  reaction. 


Fig.  54. 

Development  of  tonus  by  interference  of  sub-threshold  stimuli. 

S— Level  of  the  threshold  of  perceptible  cflect. 

The  summation  of  sub-threshold  excitation  to  a  certain  height 
oflers  very  favorable  conditions  for  the  development  of  tonus. 
(Figure  54.)  This  fact  has  been  established  for  many  kinds  of 
centers  (cardio-inhibitory  center,  vasomotor  ceiUer,  etc.).  During 
the  continuance  of  a  scries  of  stimuli,  as  we  have  already  seen, 
an  equilibrium  between  disintegration  and  replacement  soon  takes 

I  Max  Verworn:  Psychophysiologischc  Protistcnstudieii.  Expcrimcntclle  I'ntcr- 
suchungen."     Jena    1889. 

The  same:   "Die   physiologische    lUdeutung   dcs   Zcllkcrns,"      Fllugers   Arch.    Bd.   51. 

1892. 


218  IRRITABILITY 

place.  The  level  of  this  state  of  equilibrium  depends  upon  the 
relative  intensity  of  the  stimuli.  It  is  lower  in  the  case  of  strong 
and  higher  in  that  of  weak  stimuli.  This  fact  becomes  apparent 
from  the  researches  of  Thorner^  on  the  fatigue  of  medullated 
nerves  in  air.  This  investigator  showed  that  during  continued 
tetanic  stimulation  of  the  nerv^e,  the  irritability  fell  to  a  certain 
level,  at  which  it  remained  so  long  as  stimulation  persisted.  The 
irritability  decreased  to  a  new  level  when  the  strength  of  the 
stimulus  was  increased.  These  interesting  experiments  of  Thor- 
ner  show  that  the  level  reached  when  stimulation  is  continued  is 
higher  as  the  intensity  is  weaker.  It  is,  therefore,  clear  that  this 
level  in  summation  of  stimulation  beneath  the  threshold  can  be 
above  that  of  the  threshold  of  perceptible  response,  that  is,  a  per- 
ceptible tonic  excitation  may  result.  In  the  genesis  of  tonus  in 
the  muscle,  there  is  another  point  to  be  taken  into  consideration. 
Here  we  have  a  combination  of  a  heterotopic  interference  with  a 
homotopic  interference,  for  the  total  shortening  of  the  muscle  is 
brought  about  in  part  by  several  contraction  waves  which  occur 
at  various  points  at  the  same  time  and  which  follow  each  other, 
therefore  have  a  heterotopic  sequence.  If  we  consider  a  long 
stretch  of  muscle,  to  one  end  of  which  a  stimulus  is  applied,  it  will 
be  found  that  the  contraction  wave  moves  throughout  the  entire 
length.  If  after  a  certain  interval  of  time  a  second  stimulus  is 
applied,  the  resultant  wave  moves  along  the  muscle  but  does  not 
necessarily  homotopically  interfere  with  the  first.  In  short,  there 
are  two  waves  of  contraction  occurring  coincidently  in  the  muscle, 
the  muscle  is  now  more  strongly  contracted.  Frohlich^  has  made 
the  fact  intelligible  by  this  means  that  tetanic  shortening  of  a 
muscle  is  greater  than  that  of  maximal  shortening  which  can  be 
produced  by  strong  single  stimulation.  This  heterotopic  inter- 
ference dare  not  be  overlooked  in  the  genesis  of  muscle  tonus. 
If  it  is  true,  as  appears  from  the  investigations  of  Keith  Lucas,^ 

1  Tlwrner :  "Weitere  Untersuchungen  uber  die  Ermiidung  des  markhaltigen  Nerven. 
Die  Ermiidung  in  Luft."     Zeitschr.  f.  allgem.  Physiologic  Bd.  X,   1910. 

2  Fr.  IV.  Frohlich:  "Ueber  die  scheinbare  Steigerung,"  etc.  Zeitschr.  f.  allgem. 
Physiol.    Bd.   V,    1905. 

3  Keith  Lucas:  "On  the  gradation  of  activity  in  a  skeletal  muscle  fiber."  Journ. 
of  Physiology,  Vol.  XXXIII,  1905-06.  The  same:  "The  all  or  none  law  of  contraction 
of  the  skeletal  muscle-fiber."     Journ.   of  Physiology,   Vol.   XXXIII,   1909. 


INTERFERENCE  OE  EXCITA'l  loXS  219 

that  the  "all  or  none  law"  ai)i)lies  to  .striated  muscle,  then  an 
increase  of  the  contraction  from  homotopic  summation  cannot 
occur,  because  an  isobolic  system  cannot  show  an  increase  of  its 
already  maximal  excitation  by  summation.  Such  bein^'  the  case, 
the  tonic  shortening  of  striated  muscle  can  only  be  exi)lained  as 
an  expression  of  a  heterotopic  interference. 

If  we  assume  that  the  suiumation  of  sub-threshold  stimulation, 
by  increasing  excitation,  brings  about  a  state  of  e(iuilibrium  from 
below,  as  it  were,  so  also  inhibition  may  be  assumed  to  be  the 
reverse,  the  level  of  cquilil)rium  being  reached  from  above,  as  it 
were,  by  decrease  of  the  primary  excitation  from  strtjng  >tinuila- 
tion.  This  is  expressed  in  our  general  scheme  of  the  develop- 
ment of  summation  and  inhibition  resulting  from  the  effect  of  a 
series  of  stimuli.  At  the  same  time  the  first  part  of  the  curve  to 
the  fall  of  irritation  to  the  level  of  the  sub-threshold  e(|uilibrium 
can  be  shortened  to  a  minimum  by  strong  stimulation  or  greater 
frequency  of  the  same,  and  we  have  then  the  type  of  inhibition 
with  primary  excitation.  As  example  of  this  I  wish  to  again  recall 
the  strychninized  frog  which  was  used  in  the  fundamental  experi- 
ments for  understanding  of  the  theory  of  inhibition.  If  we  stinui- 
late  a  sensory  nerve  of  a  strychninized  frog,  in  which  the  refrac- 
tory period  is  already  lengthened,  with  rhythmic  single  induction 
shocks  of  slow  frequency,  the  muscle  arranged  to  make  a  graj)hic 
record  will  show  reflex  contraction  following  each  stimulus.  If. 
on  the  other  hand,  we  apply  a  series  of  stimuli,  consisting  of  single 
stimuli  rapidly  repeated,  contraction  is  produced  only  by  the  first, 
or  the  first  few  stimuli  (Figures  45  and  41),  pages  202,  2<»;}).  For 
the  succeeding  stimuli  the  centers  remain  inhibited,  because  eacli 
succeeding  stimulus  occurs  in  the  refractory  ])eriod  of  the  former. 
The  origin  of  this  inhibition  shows  us  with  particular  clearness 
how  excitation  ])roduce(l  by  each  single  stimulus  depending  upon 
the  frequency  of  the  same,  falls  rapidly  or  slowly  beneath  the 
threshold  of  perceptible  response,  in  this  case,  the  state  of  ecjui- 
librium  is  reached  which  is  maintained  by  the  following  stimuli. 
That  a  single  stimulus  is  not  entirely  without  cfTcct  ujkmi  thi^ 
state  of  equilibrium  follows  from  the  fact  that  during  the  con- 
tinuation of  the  stinmlus  a  recovery  to  the  i)oint  of  observable 


220  IRRITABILITY 

response  does  not  occur,  whereas  such  is  the  case  immediately 
upon  the  discontinuation  of  the  stimulus.  In  inhibition,  then,  the 
dissimilatory  excitation  produced  by  a  single  stimulus  falls  to  a 
low  level  as  a  result  of  the  reduction  of  irritability  and  remains 
at  this  level  continuously.  Inhibition  as  well  as  tonus  is  based 
upon  the  development  of  a  state  of  equilibrium  betzveen  excita- 
tion and  recovery,  or  disintegration  and  restitution  of  the  living 
substance  under  the  continuous  effect  of  a  rhythmic  series  of 
stimuli.  They  differentiate  themselves  essentially  by  the  height 
of  this  equilibrium,  which  is  dependent  upon  the  intensity  of  the 
stimulus. 

We  have  to  the  present  considered  only  the  simplest  conditions 
existing  as  a  result  of  the  effect  of  a  single  series  of  stimuli  and 
also  of  the  interference  of  its  individual  members.  These  ele- 
mentary conditions  are  at  the  basis  of  an  understanding  of  com- 
plicated interference  effects  which  arise  zvhen  tzvo  series  of  stim- 
uli interact.  In  that  these  processes  can  be  readily  explained  by 
the  elementary  processes  previously  described,  I  will,  therefore, 
dwell  but  briefly  on  this  subject.  From  the  standpoint  already 
taken  it  may  be  readily  presumed  what  will  happen  when  two 
series  of  stimuli  act  upon  the  same  system. 

When  there  is  interference  of  two  series  of  stimuli,  there  are 
two  resultant  possibilities.  In  one  type  the  stimuli  of  the  one  are 
active  simultaneously  with  that  of  the  other.  In  this  instance 
both  stimuli  would  act  as  a  single  stimulus  of  greater  intensity, 
and  we  have  essentially  the  same  condition  as  exists  when  a  single 
series  is  operative.  Nevertheless,  such  cases  are  practically  hardly 
realized  in  the  physiological  happenings  of  the  organism.  More 
often  a  state  exists  wherein  the  single  stimuli  of  one  series  occur 
in  the  intervals  of  the  stimuli  of  the  other.  In  these  cases  there 
is  an  increase  in  the  frequency  of  the  stimuli  applied  in  a  given 
length  of  time.  We  have  here,  then,  in  principle  the  same  condi- 
tions as  when  a  series  of  greater  frequency  is  operative.  (Figure 
55.)  The  effect  of  such  alteration  in  the  frequency  consists  in  an 
increase  of  the  velocity  of  the  development  of  summation  or  inhi- 
bition, as  the  general  scheme  (Figure  55)  has  shown  us.  Depend- 
ing upon  the  special  combination  of  the  factors  involved  in  inter- 


INTERFERF.XCE  OF  FXCITATIOXS 


221 


ferencc.  we  may  have  a  summation  of  the  exciting  eflfect  of  each 
series  of  stimuh  or  an  inhibition  of  one  series  hy  the  exciting 
effects  of  the  other  series.  If  ilie  frecjuency  of  I)oth  series  is 
essentially  different,  we  may  have  here  the  cuiuiitions  for  periodi- 
cally increasing  and  decreasing  excitations.  Nevertheless  these 
conditions  have  not  been  systematically  analyzed  and  exi)erimcn- 
tally  studied. 


s  - 

■  ;^ 

a 

V 

X 

A. 

1 

r' 

b' 

♦  ^   »           . 

■     '•    K  ■  '    K    \ 

'.    <     «    '<    \    \    '. 

•       • 

H 


FiS.  55. 


Interference  of  two  series  of  stimuli.  A  Effect  of  the  one  scries  alone.  Development  of  tonus 
by  summation.  The  dots  below  the  curve  indicate  the  points  of  time  at  which  the  stimuli 
of  the  second  series  will  operate.  B  Effect  resulting!  from  the  interference  of  both  scries. 
By  the  addition  of  the  second  series  the  frequency  has  been  doubled.  The  result  consists 
in  an  inhibition. 

The  greatest  number  of  instances  of  the  interference  of  two 
series  of  stimuli  have  been  given  to  us  by  investigation  of  the 
physiology  of  the  nervous  system.  In  the  functionation  of  the 
nervous  system  the  fact  that  two  series  of  stimuli  from  ditlerent 
tracks  affect  the  same  ganglia  i)lays  a  very  important  role.  It 
is  this  to  which  Sherrington^  has  alluded  as  "ihc  princ'xplc  of 
the  common  path."  Where  two  nervous  excitations  involve  the 
same  paths,  there  arises  an  interference  of  the  effect  of  the  two 
series  of  stimuli,  for  the  impulses  in  the  nervous  system,  as 
already  stated,  possess  a  rhythmic  character.  This  princii)le  has 
a  broad  application  in  the  phenomena  of  association  in  the  cere- 
bral cortex.  The  simpler  and,  therefore,  the  most  easily  under- 
stood cases  are,  however,  in  the  spinal  cord.  The  motor  neurons 
of  the  anterior  horns  of  the  spinal  cord  are  the  junction  of  a 


\  Sherrington :     "Ueber     das     Zusammcnwirkcn     dcr     RucWcnmarksrcflcxc     und     di* 
Princip  der  gemeinsamen  Strecke."     Ergebnissc  dcr  Physiologie.     Jahr.   IV.   l^^OS. 


222  IRRITABILITY 

great  number  of  tracks,  for  example,  the  sensory  neurons  of  the 
spinal  cord  at  different  levels,  the  neurons  of  the  cerebellum,  the 
pyramidal  tracks  from  the  motor  areas  of  the  cerebral  cortex, 
etc.  On  the  contrary,  for  example,  the  sensory  neurons  of  the 
spinal  cord  are  strictly  "private  paths"  in  the  sense  of  Sherring- 
ton, for  excitation  can  enter  by  this  means  only  from  the  special 
paths  of  the  spinal  ganglia  and,  therefore,  from  the  periphery. 
The  motor  neurons  of  the  anterior  horns  offer,  therefore,  excel- 
lent opportunities  for  the  experimental  investigation  of  the  inter- 
ference of  two  series  of  excitations  which  enter  by  different 
paths.  The  spinal  cord  consequently  has  become  a  much-used 
object  of  investigation  for  this  purpose.  In  fact,  we  can  observe 
and  produce  all  types  of  interference  in  the  spinal  cord.  These 
conditions  have  been  quite  thoroughly  investigated  by  Sherring- 
ton'^ and  his  coworkers  on  the  dog,  and  Frohlich,-  Veszi,^  Tiede- 
mann'^  and  Satake^  on  the  frog. 

A  summation  of  two  excitations  was  observed  already  by 
Exner.  This  investigator  connected  the  abductor  pollicis  of  the 
rabbit  with  an  apparatus  for  making  graphic  records.  He  then 
stimulated  first  the  paw  and  then  the  motor  areas  of  the  cerebral 
cortex  with  faradic  shocks,  the  intensity  of  which  was  just  suffi- 
cient to  bring  about  perceptible  effect.  If  both  stimuli  were 
simultaneously  operative,  an  increase  in  the  response  was  ob- 
served. Even  when  the  stimuli  were  sub-threshold  in  type,  as  a 
result  of  summation  there  was  a  perceptible  muscle  contraction. 
( Figure  56.)  Exner  had  at  that  time  referred  to  this  increase  of 
the  response  as  *'Bahnung"  (reinforcement).  However,  the  word 
"Bahnung"  has  more  than  one  meaning,  for  processes  of  various 
types  are  involved  in  this  term.    Thus  writers  have  differentiated 

1  Sherrington:  "The  integrative  action  of  the  nervous  system."     New  York  1906. 

2  Fr.  W.  Frohlich:  "Der  Mechanismus  der  nervosen  Hemmungsvorgange."  Med. 
Natur.  Arch.  Bd.  I,  1907.  The  same:  "Beitrage  zur  Analyse  der  Reflexfunction  des 
Riickenmarks,  etc."  Zeitschr.  f.  allgem.  Physiologie  Bd.  IX,  1909.  The  same:  "Das 
Princip  der  scheinbaren  Erregbarkeitssteigerung."     Ibid. 

3  Julius  Vessi:  "Der  einfachste  Refiexbogen  im  Riickenmark."  Zeitschr.  fur  allgem. 
Physiol.   Bd.    IX,    1910. 

4  Tiedemann :  "Untersuchungen  iiber  das  absolvite  Ref ractarstadium  und  die 
Hemmungsvorgange  im  Riickenmark  des  Strychninfrosches."  Zeitschr.  f.  allgem. 
Physiologie   Bd.   X,   1910. 

5  Satake:  The  researches  are  not  yet  published. 


INTERFERENCE  OF  EXCITATIONS 


223 


real  and  apparent  ''Bahnungen."  On  account  of  this  lack  of  clear- 
ness in  the  meaning  of  the  term  "Bahniing."  I  wish  to  discard  its 
use  as  it  is  not  at  all  essential.  We  will  si)eak  simply  of  a  summa- 
tion of  excitation,  for  here  it  is  sinij)!)'  a  question  of  summation 
of  two  excitations  of  the  motor  cells  of  the  si)inal  cord. 


-» 


~v 


r\rArt-ir\rArArAr\r-\i 


If 

s 


-^ 


T 


J L 


iiMnrtwmi 


H 


AruW'dVlrtrts^  rUljAnrtrv 


Fig.  56. 


B 


Summation  of  two  excitations  in  the  rabbit.  The  one  proceeds  from  the  paw.  the  other  frf)m 
the  motor  sphere  of  the  cerebral  cortex.  S  Time  in  seconds.  Pf  Stimulation  of  the  paw. 
//—Stimulation  of  the  motor  sphere.  Af— Contractions  of  the  abductor  poilicis.  '.\fter 
Exner.) 


M 


S 


Frohlich  has  shown  that  summation  of  two  excitations  upon  a 
motor  cell  of  the  anterior  horn  coming  by  way  of  different  paths 
is  more  readily  obtained  when  the  stimuli  are  somewhat  strong, 
or  when  the  duration  of  the  excitation  processes  in  the  ganglion 
cells  are  somewhat  prolonged  by  fatigue. 

On  the  other  hand,  the  conditions  for  the  production  of  inhibi- 
tion are  favored  when  the  intensity  of  the  series  of  stimuli  is  weak. 
Here  it  is  a  question  of  the  development  of  a  relative  refractory 
period  for  the  weak  stimuli  by  increase  in  their  frecjuency.  .\ 
relative  fatigue  of  the  motor  ganglion  cells  for  weak  stimuli 
rapidly  occurs,  and  there  develops  a  state  of  equilil)rium  beneath 
that  of  the  threshold  of  perceptible  effect  throughout  the  con- 
tinuation of  stimulation.  Veszi  succeeded  in  isolating  these  types 
of  summation  and  inhibition  in  the  spinal  cord.  His  method  con- 
sisted in  cutting  the  posterior  roots  of  the  spinal  cord  of  the  frog 
and  stimulating  faradically  the  central  ends,  and  at  the  same  time 
graphically  recording  the  response  of  the  gastrocnemius  muscle. 
Upon  faradic  stimulation  of  the  ninth  posterior  root,  one  obtains 
tetanic  reflex  contraction  of  this  muscle.     When  the  tenth  i>oste- 


224 


IRRITABILITY 


rior  root  is  then  stimulated,  tetanus  is  also  produced  but  of  some- 
what shorter  duration.  If,  while  obtaining  tetanus  reflexly  by 
stimulation  of  the  ninth  root,  a  faradic  current  of  short  duration 
and  not  too  weak  is  applied  to  the  tenth  root,  then  a  summation 
of  excitation  occurs,  an  increase  in  the  reflex  contraction. 
(Figure  57,  A  and  B.)     When,  on  the  other  hand,  the  tenth  root 


B 

Fig.  57. 

Summation  of  two  excitations  in  the  spinal  cord  produced  by  stimulation  of  the  ninth  and 
tenth  posterior  root.  Lower  line  indicates  faradic  stimulation  of  the  tenth,  upper  line 
of  the  ninth  root. 


INTERFERENCE  OF  EXCITATIONS 


225 


is  stimulated  with  weak  shocks,  one  can  ol)tain  an  increase  of  the 
tetanus  of  short  (kiration  followed  by  inhibition.  Here,  as  the 
result  of  interference,  we  have  an  instance  of  inhibition  with  pri- 
mary tetanus.     (Figure  58.)     W  hen  the  tenth  root  is  stimulated 


B 

Fig.  58. 


with  very  weak  shocks,  inhibition  of  the  tetanus  produced  simul- 
taneously from  the  ninth  root  occurs  without  primary  summation. 
(Figure  59.)  The  fact  that  two  series  of  stimuli,  both  of  which 
produce  dissimilative  excitation,  bring  about  an  inhibition  by 
their  combined  action,  is  sufficient  to  show  the  untcnability  of 
the  Gaskcll-Hcrimj  hypothesis,  that  inhibitory  i)roccsscs  result 
from  assimilatory  excitation.  It  would  be  impossible  to  under- 
stand how  two  dissimilatory  exciting  stimuli,  by  their  simulta- 
neous action,  could  l)ring  about  assimilatory  e\(Mtntion.     When 


226  IRRITABILITY 

the  eighth  or  the  seventh  root  is  stimulated  with  stronger  faradic 
shocks  during  the  time  when  tetanus  is  produced  reflexly  by 
faradic  stimulation  of  the  ninth,  an  inhibition  is  practically  always 
obtained.  Indeed,  faradic  currents  that  are  so  weak  as  to  be  far 
below  the  threshold  of  perceptible  response  bring  about  when 
applied  to  the  seventh  or  eighth  root  a  decided  inhibition  of  the 
tetanus,  brought  about  by  simultaneous  stimulation  of  the  ninth 
root.  The  inhibitory  effect  of  weak  sub-threshold  excitations 
are  here  particularly  apparent.  This  inhibition  resulting  from 
excitation  far  below  that  of  the  threshold  of  perceptible  response 


Fig.  59. 

is  a  common  occurrence  in  the  functional  activities  of  the  central 
nervous  system.  In  various  parts  of  the  nervous  system,  the 
excitation  in  its  conduction  is  weakened  when  passing  through 
intervening  ganglion  stations  so  that  it  has  undergone  a  strong 
decrement  before  reaching  the  responding  structure,  where  an 
inhibitory  effect  may  be  manifested.  In  this  connection  it  is  of 
interest  that  the  reciprocal  "antagonistic  reflexes"  discovered  by 
Sherrington,^  who  recognized  their  importance  in  the  functional 
processes  of  the  nervous  system,  can  be  explained,  as  Frohlich 
showed,  upon  this  principle  of  inhibition  resulting  from  weakened 
excitation.      On   the   basis    of    numerous    investigations    in    the 

1  Sherrington:  "Experimental  note  on  two  movements  of  the  eye."  Journ.  of  Physi- 
ology XVII,  1895.  The  same:  "On  the  reciprocal  Innervation  of  antagonistic  mus- 
cles."    Proceed,   of  the   Royal   Soc,    1897. 


INTERFERENCE  OF  EXCITATIONS 


227 


Gottingen  laboratory  as  well  as  lluit  of  PxHin'  \vc  have  come  to 
look  upon  the  reflex  arc  in  the  spinal  cor^l  as  consisting  of  the 
following  elements:  a  neurone  in  the  -i)inal  ^anglicjn.  a  neurone 
in  the  posterior  horn  and  a  motor  neurone  in  the  aiUerior  horn. 
This  is  the  most  direct  route  between  the  i)oint  of  stinuilation 
and  that  of  the  responding  organ  of  a  unilateral  retk-x.  (  I-'igurc 
60.)     It  is  known  that  the  excitation  becomes  weaker  in  passing 


Fig.  60. 


Scheme  of  the  simplest  unilateral  reflex  arc  of  the  spinal  cord 


from  the  entrance  of  the  excitation  into  the  spinal  cord  to  the 
motor  elements  of  a  lower  level  on  the  same  side  or  to  those  on 
the  opposite  side.    In  order  to  obtain  a  response  a  stronger  stimu- 

l  Max  J'eru'orn:  "Die  einfachstcii  RcflcxwrRf  im  Kuckcnmark."  Zentralbl«((  t. 
Physiologic  Bd.  XXIII.  Ticdemann :  "I'litcrsuchutiKcn  ubcr  da>  absolute  Rcfractar- 
stadium  und  die  IIcmmuiiKsvorgaiiKC  im  Kuckcnmark  dc»  StrychninfrojMrhc*.*'  Zcil»chr. 
f.  allgem.  Physiologic  Bd.  X.  1910.  Julius  I'^ssi:  "I)er  cinfachste  Rcflcxbogcn  im 
Riickenmark."  Zeitschr.  f.  allgem.  Physiologic  Bd.  XI.  NIO.  Oii»iim<i  "rcl»rr  die 
asphyktische  Lahmung  des  Riickcnmarks  strychninisiertcr  Fro»chc."  7-"*  hr.  (. 
allgem.    I'hysiol.    Bd.    XII,    1911.      Satakc:   Not   yet    published. 


228 


IRRITABILITY 


lus  is  necessary.  Here  the  weakening  of  the  excitation  as  well  as 
the  prolongation  of  the  reaction  time  is  brought  about  by  the 
introduction  of  intercalated  neurones.  The  reflex  arc  contains 
more  stations.     (Figure  61.)     If  we  accept  the  most  plausible 


Fig.  61. 

Scheme  of  the  simplest  reflex  arc  from  one  to  the  other  side,  and 
from  a  higher  to  a  lower  level. 


assumption  that  the  central  connection  of  antagonistic  muscles 
possesses  like  relations,  then  the  effects  discovered  by  Sherrington 
are  self-explanatory.  In  this  case  stimulation  of  the  sensory 
path,  which  brings  about  a  strong  reflex  excitation  of  the  motor 
neurons  of  the  anterior  horns  controlling  a  muscle,  at  the  same 
time  stimulates  the  antagonistic  muscle  with  sub-threshold  stimuli. 
The  result  of  this  as  shown  by  the  experiments  of  Veszi  is  not  a 
motor  response  of  the  antagonists,  but  an  inhibition  if  the  motor 
neurons  of  the  antagonists  are  at  the  time  in  a  state  of  excita- 
tion.    It  is,  therefore,  understandable  that  reflex  excitation  of  a 


INTERFERENCE  OF  EXCITATIONS  229 

muscle  under  normal  conditions  of  irrilabililv  has  an  inhibitory 
effect  on  its  anta^^onist. 

Finally,  I  wish  to  conclude  this  discussion  on  tlic  origin  of 
central  inhibition  and  its  dependence  ui)on  the  strength  of  the 
stimulus  by  referring  to  a  |)oint  which  apparently  is  contradic- 
tory. We  have  already  met  with  the  fart  that  series  of  stimuli 
by  their  interference  in  tlie  nervous  system  may  have  different 
effects  depending  upon  their  intensity;  if  this  is  strong,  we  obtain 
summation  of  excitation,  if  weak  an  inh.ibition.  The  question 
may  be  asked,  how  is  it  i){)ssil)le  that  a  weak  stimulus  can  have 
a  different  effect  when  it  is  believed  that  the  nerve  as  an  isol>olic 
system  responds  to  intensities  of  all  gradations  to  the  same  extent, 
namely,  w^ith  maximum  excitation?  If  the  "all  or  none  law"  is 
applicable,  then  the  same  intensity  of  excitation  is  always  carried 
to  the  centers  and  yet  we  see  that  various  kinds  of  resiH:)nses 
follow  various  intensities  of  stinuilation.  Here,  indeed,  is  a 
difficulty  which  has  not  as  yet  been  explained.  Naturally  between 
the  two  facts  there  can  be  no  contradiction,  liut  the  question 
arises,  how  are  we  to  bring  them  into  harmony?  Two  entirely 
different  possibilities  present  themselves.  If  the  various  inten- 
sities of  stimulation  always  bring  about  excitation  of  the  same 
strength  and  we  see  in  spite  of  this  that  various  intensities  of 
stimulation  produce  various  kinds  of  effects,  then  we  must  think 
of  the  possibility  that  various  intensities  of  stinuilation  bring 
about  some  other  effect  than  that  of  variations  in  intensity 
in  the  course  of  the  w^ave  of  excitation.  In  this  comiection 
variations  in  the  time  involved  nuist  be  taken  into  consideration. 
One  might  think  that  strong  stimuli  may  develop  a  longer  wave 
of  excitation  than  such  of  zucak  intensity.  Cotcli^  tested  tliesc 
questions  experimentally  with  comi)letely  negative  results.  A  single 
strong  stimulus  does  not  result  in  an  excitation  ditTering  in  its 
course  from  that  of  a  weak  stimulus.  But  there  is  another  possi- 
bility that  requires  testing.  This  was  brought  to  light  !)y  the 
investigation  of  Thorucr-  on  the  fatigue  of  the  nerve.     His  invcs- 

iGotch:  "The  submaximal  electrical  rcsi)onsc  of  nerve  to  •  tiriKlr  »»inmhi« '* 
Journ.   of   Physiology,   Vol.    XXVIII.    1902. 

•  2  Thorner:  "Wcitere  UntersuchtinRen  iibcr  die  ErmrnlunK  de»  markhalligen  Ncrrcn: 
Die  Ermvidung  in  Luft."  etc.     Zeitschr.   f.  allRem.  Physiologie  Bd.   X.   1910. 


230  IRRITABILITY 

tigations  showed  that  in  a  normal  nerve  in  air  the  first  typical 
beginning  of  fatigue  resulting  from  faradic  stimulation  can  be 
demonstrated  in  the  characteristic  summation  of  excitations. 
This  is  shown  by  the  nerve  after  fifteen  minutes  of  stimulation 
with  faradic  shocks  applied  for  short  intervals.  The  irritability, 
when  tested  with  single  induction  shocks,  is  at  the  same  time 
reduced.  Thereby  the  amount  of  fatigue  of  the  nerve,  that  is, 
the  amount  of  the  reduction  of  irritability,  is  dependent  upon  the 
strength  and  frequency  of  stimulation  producing  fatigue.  When 
the  nerve  is  stimulated  with  weak  faradic  shocks  of  a  slow  rate 
of  frequency,  there  is  a  slight  or  a  complete  absence  of  the  reduc- 
tion of  irritability.  On  the  other  hand,  if  the  nerve  is  fatigued 
with  strong  faradic  shocks  of  great  frequency,  the  irritability 
falls  very  considerably.  This  shows  that  when  the  nerve  is  stimu- 
lated for  a  longer  time,  even  under  conditions  favorable  to  the 
supply  of  oxygen,  a  diminution  of  irritability  occurs  and  with  it 
naturally  an  actual  diminution  of  the  wave  of  excitation,  a  diminu- 
tion the  intensity  of  which  becomes  greater  as  the  strength  of 
the  stimulus  increases.  In  other  words,  long-continued  faradic 
stimulation  converts  the  nerve  from  a  system  isobolic  in  character 
to  that  which  is  heterobolic  in  that  the  intensity  of  the  excitation 
which  is  conducted  differs  depending  upon  the  intensity  of  the 
stimulus.  We  have  found  other  cases  in  the  investigation  of  the 
nervous  system  in  which,  as  in  fatigue,  an  isobolic  is  converted 
into  a  heterobolic  system.  Veszi^  has  shown  that  the  centers  of 
the  strychninized  frog,  which  are  isobolic  in  character,  when 
fatigued  by  weak  faradic  stimuli  can  be  brought  to  react  again 
when  the  faradic  stimulation  is  increased.  According  to  this  and 
other  experiments  of  a  like  nature,  it  is  beyond  doubt  that  an  iso- 
bolic system  during  the  refractory  period  may  assume  a  hetero- 
bolic character,  and  only  after  completion  of  the  refractory  period 
and  entire  recovery  of  the  equilibrium  of  metabolism  does  the  iso- 
bolic character  return.  This  permits  us  to  understand  the  charac- 
teristic properties  of  an  isobolic  system  more  accurately  and  pre- 
cisely than  has  thus  far  been  possible.     The  "all  or  none  law" 

1  Vessi:  "Zur  Frage  des  Alles  oder  Nichtsgetzes  beim  Strychninfrosche."     Zeitschr. 
f.  allgem.  Physiologic  Bd.  XII,   1911. 


INTERFERENCE  OF  EXCITATIONS  231 

with  its  associated  i)roi)crtics,  such  as  the  conductivity  without 
decrement  and  tlie  incapahility  of  summatin^'  excitations,  have 
in  a  system  of  this  character  only  relative  valichty.  Tlicy  arc 
realized  only  in  the  state  ui  an  ecjuilihrium  of  nietabolism.  Only 
when  the  stimuli  follow  each  other  at  interval^  greater  than  the 
duration  of  the  refractory  period  is  there  a  resi>onsc  of  equal 
extent  to  stimuli  of  all  intensities  which  are  above  the  threshold. 
During  the  refractory  i)eriod  and  conse^juently  in  fatipue, 
asphyxia,  cooling  and  narcosis,  etc.,  in  short,  in  all  states  in  which 
the  refractory  period  is  ])rolonged  this  system  loses  its  isoholic 
properties  and  becomes  heterobolic.  In  order  that  there  may  not 
be  a  misunderstanding,  we  will  consider  more  in  detail  the  capa- 
bility in  this  state  of  summation  of  excitations.  When  we  refer 
to  a  summation  of  excitation  of  such  a  .system  under  tiie  intUiencc 
of  one  of  these  factors,  we,  of  course,  at  no  time  mean  an  increase 
of  response  beyond  that  of  the  degree  of  excitation  which  exists 
in  an  isobolic  system  in  a  normal  state  consequent  uiK)n  the  aj)pli- 
cation  of  a  single  stimulus,  for  this  degree  of  excitation  is  maxi- 
mal. We  refer  rather  to  a  summation  which  has  become  reduced 
as  a  result  of  fatigue. 

On  the  basis  of  these  facts  it  is  readily  understood  when  a  icvcl 
of  equilibrium  of  lower  intensity  has  been  reached  that  excita- 
tion produced  by  weak  faradic  stimulation  must  have  weaker 
effects  than  when  strong  stimuli  are  api)licd.  for  when  the  system 
assumes  a  heterobolic  type  as  the  result  of  relative  fatigue  weak 
stimuli  bring  about  weak,  and  strong,  stronger  excitation.  Conse- 
quently, during  interference  induced  by  a  second  series  of  excita- 
tions, in  the  first  case  we  have  the  conditions  favorable  for  inhi- 
bition, in  the  second  for  those  of  summation.  If  we  also  assume 
that  this  characteristic  alteration  of  the  isobolic  character  of  the 
elementary  nerve  fibers  which  has  been  shown  to  occur  in  fatigue, 
as  seen  when  continued  faradic  stimulation  is  employed,  develops 
immediately  after  the  beginning  of  stimulation  then  wc  can 
readily  understand  the  various  kinds  of  effects  produced  by  inter- 
ference  observed  in  the  retlcx  response  following  weak  and  strong 
faradic  stimulation  to  the  ditTerenl  nerves  in  spite  of  the  fact  that 
the  nerve  in  the  state  of  rest  is  a  svstem  isobolic  in  tyjK!.    Kx|>cri- 


232  IRRITABILITY 

mental  evidence,  therefore,  must  be  brought  forward  to  show 
that  faradic  stimulation  of  short  duration  produces  the  above- 
mentioned  alteration  in  the  character  of  the  system.  Thorncr  in 
his  experiments  on  the  nerve  stimulated  it  faradically  at  least  four 
minutes  and  always  found  after  this  that  excitation  was  reduced. 
After  shorter  intervals  of  stimulation  Thorner  made  no  test  of 
the  state  of  excitation.  It  is,  however,  highly  probable  that  a 
reduction  of  excitation  is  much  more  quickly  reached.  Indeed, 
we  are  unavoidably  compelled  to  accept  the  assumption  that  even 
after  the  first  single  stimulus  of  the  faradic  current,  alterations 
of  a  slight  degree  are  present  which,  after  repeated  stimulation, 
become  constantly  greater  and  give  to  the  system  a  heterobolic 
character.  As  a  result  of  fatigue,  as  we  have  already  seen,  the 
refractory  period  becomes  more  and  more  prolonged.  As  the 
individual  shocks  in  faradic  stimulation  follow  each  other  at 
regular  intervals,  a  necessary  consequence  is  that  the  shocks  are 
operative  before  the  refractory  period  has  completely  disap- 
peared, otherwise  Thorner  could  not  have  obtained  fatigue  pro- 
duced by  continued  stimulation.  The  intervals  of  the  individual 
shocks  must  be  somewhat  shorter  than  the  duration  of  the  refrac- 
tory period,  even  in  fatigue  of  a  very  slight  degree.  It  is  very 
interesting  in  this  connection  that  Thorner  invariably  obtained 
positive  evidences  of  fatigue  by  the  application  of  stimuli  at  the 
rate  of  10-12  per  second.  When  the  number  of  stimuli  per  second 
was  less  than  this  the  above-mentioned  result  was  not  always 
obtained.  From  this  we  can  easily  estimate  the  refractory  period 
of  the  nerve,  which  is  present  after  reaching  a  state  of  equilib- 
rium under  certain  conditions.  If  we  assume  ten  stimuli  per 
second  to  be  the  number  required  to  produce  slight  fatigue  when 
stimulation  is  prolonged,  we  can  conclude  that  the  refractory 
period  in  this  state  is  somewhat  longer  than  one  tenth  of  a  second. 
Even  though  Gotch  in  his  investigations  already  cited  placed  the 
refractory  period  of  the  normal  nerve  at  about  .005  second,  this 
statement  is  in  no  way  contradictory  to  the  figure  which  we  have 
just  given.  Gotch  measured  simply  the  duration  of  the  absolute 
refractory  period  of  the  normal  nerve,  in  other  words,  the  dura- 
tion of  the  period  in  which  no  excitation  at  all  could  be  brought 


INTERFERENCE  OF  EXCITATIONS  '^33 

about.  On  the  contrary,  my  estimate,  based  upon  tlic  invcstij^a- 
tions  of  Thorncr,  refers  to  the  totnl  refraelory  |)crioc!  of  the 
nerve,  that  is,  to  the  point  of  complete  recovery  of  the  e(|uihbrium 
of  metabohsm  and  of  tlie  specific  irrital)ihiy.  Experimental  pr(K)f 
of  this  assuniptiun  is  already  under  way. 

I  have  endeavored  to  show  the  elemenuiry  principles  at  uie 
basis  of  these  extremely  varied  interference  effects  and  to  make 
a  few  generalizations  concerning  the  complicated  conditions  here 
concerned,  it  has  been  shown  that  a  great  number  of  interfer- 
ence efifects  possess  characteristics  in  common  if  one  takes  into 
consideration  the  process  occurring  in  the  cour>e  of  a  single 
excitation.  The  altered  state  which  exists  in  living  substance 
until  the  complete  disappearance  of  excitation  is  the  basis  ujKDn 
which  to  explain  the  altered  effects  produced  by  a  second  stimulus*. 
This  state  alters  during  the  whole  course  of  the  first  stimulus 
until  the  original  eciuilibrium  of  the  luetabolism  of  rest  is,  by  self- 
regulation,  again  reached.  It  is.  therefore,  self-evident  that  the 
second  stimulus  must  have  different  etYects  depending  uiK)n  the 
momentary  state  of  the  living  system  at  the  tiiue  of  its  ai)plica- 
tion.  The  state  of  the  system  differs  depending  on  the  length 
of  the  interval  in  which  the  second  stimulation  follows  the  first. 
The  most  important  factor  is  the  phase  of  the  excitation  period 
and  the  reduction  of  irritability.  The  second  important  factor 
is  the  intensity  of  the  second  stimulus;  the  relation  of  the  two 
with  each  other  determines  the  response.  I'ut  the  specific  prop- 
erties of  the  given  systems  must  also  be  taken  into  consideratit)n. 
It  is  important  to  know  if  the  living  system  possesses  isolH)lic 
properties,  that  is,  every  intensity  of  stinuilation  produces  a 
maximal  liberation  of  energy,  or  if  it  possesses  a  heterol>olic 
character,  that  is,  stinuili  of  different  strength  bring  al)OUt  the 
liberation  of  different  amounts  of  energy.  It  is  further  imjKir- 
tant  to  know  the  rapidity  of  reaction,  whether  the  sy.stem  rapidly 
or  slowly  fatigues.  In  all  cases  it  dei)ends  whether  the  second 
stimulus  produces  a  perceptible  excitation  or  whether  it  occurs 
in  the  refractory  period  and  jjroduces  no  i)erceptible  effect.  I'jK^n 
these  factors  dei)end  the  results  of  the  interference  of  two 
rhythmic  series  of  stinudi.  whether  a  summation  or  inhibition  of 


234  IRRITABILITY 

excitation  takes  place.  Here  is  the  key  to  the  understanding  of 
the  great  variety  of  interference  effects.  By  determination  of 
these  various  factors  in  a  given  case  and  their  sequence,  we  can 
anticipate  the  nature  of  the  interference  which  will  follow.  The 
complex  actions  brought  about  by  the  various  factors,  which  we 
cannot  at  first  clearly  understand,  can  be  at  once  interpreted  as 
soon  as  we  convert  them  into  their  elements. 


CHAPTER    IX 
THE  IM<()CKSSRS  ol-  I)!:i'RF.SSTO\ 

Contents:  Necessity  of  cellular  pliysioIoKical  analysis  of  toxic  depres- 
sions by  pharmacology-  Apparent  variety  of  prcnresses  of  detiression. 
Depression  of  oxydative  disintCKration  as  the  most  cxtcnde^l  principle 
in  the  processes  of  depression.  Asphyxiation,  fatigue,  heal  depres- 
sion, as  a  consequence  of  restriction  of  oxydative  disintcKration. 
Narcosis.  Theories  of  narcosis.  The  alteration  of  specific  irritability 
and  conductivity  in  narcosis.  Depression  of  oxydative  processes  in 
narcosis.  Asphyxiation  of  livin^^  substance  when  oxygen  is  present 
during  narcosis.  Persistence  of  ant)xydative  disintegration  in  nar- 
cosis. Increase  of  the  same  by  stimuli.  Depression  by  narcosis  as 
a  form  of  acute  asphyxiation.  Hypothesis  on  the  mechanism  of 
depression  of  oxygen  exchange  i)y  narcotics.  Possibility  of  com- 
bining the  facts  with  the  observations  of  Meyer  and  Overton. 

The  processes  of  excitation  of  all  the  effects  of  stinuihilion  arc 
those  which  have  invariably  claimed  place  in  the  inlere>t  of  phys- 
iologists. The  study  of  the  i)rocesses  of  depression,  on  the  other 
hand,  has  remained  more  or  less  in  the  background.  Tliis  is 
readily  understood  when  it  is  considered  how  much  more  apparent 
the  processes  of  excitation  are  than  those  of  dei)ression.  Never- 
theless, these  latter  possess  no  less  imi)ortance  for  the  course 
of  vital  phenomena  than  those  of  excitation.  Without  dei)res- 
sion  no  excitation  can  take  i)lace  in  the  vital  activity  of  the  org:ui- 
ism,  for,  as  we  have  seen,  every  excitation  is  secondarily  ft>l- 
lowed  by  a  refractory  period.  To  this  must  be  added  the  great 
number  of  primary  depressions,  directly  brought  about  by  ll)e 
most  varied  stimuli,  such  as  cold,  want  of  oxygen,  poisons,  etc., 
without  the  presence  of  a  jireceding  excitation.  Thus  it  is  essen- 
tial that  the  processes  of  (le])ression  sliould  be  studied  with  no 
less  interest  than  those  of  excitation,  and  it  is  much  to  be  desired 
that  the  former  should  receive  a  more  detailed  analysis  than  has 
up  to  now  been  the  case,     b'ven  as  it  is.  extensive  material  has 


236  IRRITABILITY 

been  obtained  for  the  analysis  of  this  group  of  reactions.     With 
the  closer  study  of  the  process  of  excitation  the  facts  in  connec- 
tion with  the  refractory  period  and  fatigue  make  it  necessary 
that   the   processes    of    depression   be   taken   into    consideration. 
Toxicology    and    pharmacology    likewise    furnish    innumerable 
effects  of  depression  produced  by  poisons  and  drugs.     Unfortu- 
nately the  investigation  of  these  reactions  has  been  in  the  main 
purely  superficial.     This  arises  from  the  recency  of  the  devel- 
opment of  these  sciences.     Even  later  than  physiology  they  are 
only  now  beginning  to  extend  their  investigations,  directed  up  to 
the  present  to  the  grosser  organic  reactions,  to  the  cellular  analysis 
of  the  effects  of  poisons.     How  rarely  we  find  instances  in  which 
the  effect  of  some  drug  is  studied  at  the  point  of  attack  and  sys- 
tematically  followed  to  the  specific  cell   form,   and  its  primary 
excitating  or  depressing  effect  on  this  or  that  constituent  process 
of  the  metabolic  activities  ascertained.     And  how  great,  on  the 
other  hand,  is  the  number  of  "medicines"  making  their  appear- 
ance each   year   in  pharmacology   of   which   nothing   further   is 
known  than  a  few  secondary  effects  on  the  action  of  the  heart, 
the  blood  pressure,  the  secretion  and  excretion  and  on  some  other 
outwardly  perceptible  organic  actions !    This  deplorable  condition 
of  present-day  pharmacology  must  be  ascribed  to  the  regrettable 
circumstances  that   pharmacological   research   is  only   in   a  very 
small  degree  the  result  of  careful  investigations,  carried  out  by 
biologically  and  chemically  trained  pharmacologists,   but   is   for 
the  most  part  undertaken  at  the  instigation  of  chemical  manu- 
facturers.     This    eager    haste    to    obtain    superficially    practical 
results  has  lessened  in  great  degree  the  interest  in  the  close  and 
painstaking  theoretical  analysis  of  reaction  to  poisons.     Thus  it 
happens  that,  in  spite  of  the  numberless  examples  of  the  depress- 
ing effects  of  poisons  discovered  by  pharmacologists,  it  is  only 
in  rare  instances  that  the  physical  nature  of  these  processes  is 
more  closely  studied.     Therefore,  investigation  in  pharmacology 
and  toxicology  in   so   far  as  they  are  carried  out   in   a   purely 
scientific  spirit  and  not  influenced  by  the  desire  for  merely  super- 
ficial results,  may  find  here  a  wide  field  of  research  work,  rich 
in  future  promise.     It  is  from  such  investigation  that  we  may 


THE  PROCESSES  OF  DEPRESSION  237 

expect  an  abundance  of  material  for  the  closer  analysis  of  the 
processes  of  depression.  For  ihc  j)rcsent.  however,  we  nui^l 
restrict  ourselves  to  the  consideration  of  some  individual  cases 
which  have  been  studied  somewhat  more  in  detail  by  physiolo- 
gists. 

Simple  reflection  shows  the  possibility  that  depression,  tlial  is. 
the  retardation  of  the  n(jrinal  vital  i)roccsses,  can  be  broujjhi 
about  in  various  ways.  As  on  the  one  hand  the  normal  metab- 
olism of  rest  is  composed  of  very  numercnis  chemical  constituent 
processes,  and  on  the  other  hand  the  closest  inlerde|>cndciicc 
exists  between  these  individual  constituent  processes,  it  follows 
that  every  factor  which  increases  or  retards  even  one  of  these 
must  secondarily  influence  the  course  of  the  entire  activity. 
Hence  a  wide  range  of  possibilities  exists  for  the  processes  of 
depression.  As  the  complicated  works  of  a  cl(x"k  can,  by  the 
stopping  of  a  single  moving  part,  be  brought  to  a  standstill,  so  in 
like  manner  the  metabolic  activity  can  be  depressed  by  very 
different  constituent  members.  In  spite  of  this  we  have  every 
reason  to  assume  that  the  greater  number  of  all  |)rocesses  of 
depression  result  from  the  primary  etTect  of  one  or  a  few  con- 
stituent members.  A  primary  simultaneous  depression  of  all  or 
at  least  of  numerous  constituent  processes  of  the  entire  metab- 
olism may  only  be  assumed  as  ])ossil)le,  resulting  from  decrea.se 
of  temperature  within  certain  limits.  lUu  e\cn  in  the  case  of 
''cold  depression"  it  is  not  probable,  owing  to  the  great  etTect  of 
every  alteration  in  the  relations  of  masses  in  the  cell,  that  depres- 
sion is  solely  the  manifestation  oi  a  uniform  retardation  of  all 
individual  constituent  metabolic  processes.  If.  therefore,  the 
greater  part  of  the  processes  of  depression  are  brought  al)OUt  by 
the  primary  effects  of  an  individual  constituent  i)rrK*ess.  then  the 
possibility  must  be  admitted  that  any  com])onent  of  the  chain  can 
by  the  means  of  some  specific  external  intUience  form  the  starting 
point  for  a  depression.  The  iunni)cr  of  the  various  kinds  of 
processes  of  depression  would  be.  therefore,  enormous.  The 
knowledge  obtained  up  to  the  present  shows,  however,  that  this 
variety  is  not  quite  as  great  as  the  above  facts  luight  lead  one  to 
expect.     Even  though   future  investigation  will  certainlv  nnt  do 


238  IRRITABILITY 

away  with  the  assumption  of  the  existence  of  the  most  manifold 
physical  types  of  depression,  the  analysis  of  a  few  processes  which 
have  been  studied  up  to  now  demonstrates  the  singular  fact  that 
a  number  of  these  which  are  brought  about  by  quite  different 
external  factors,  are  based  on  an  absolute  uniformity  of  their 
mechanism.  As  we  have  previously  seen,  a  certain  constituent 
of  the  metabolic  chain  can  be  excitated  primarily  by  very  different 
kinds  of  stimuli.  In  like  manner  there  exists  in  metabolic  activity 
a  certain  point  of  predilection  for  different  kinds  of  stimuH,  from 
which  their  depressing  effects  proceed.  Here  the  highly  interest- 
ing fact  is  shown  that  this  point  of  predilection,  which  represents 
that  of  the  most  frequent  attack,  is  the  same  for  excitating  as  for 
depressing  stimuli.  These  are  the  oxydative  processes.  As  our 
knowledge  of  the  reactions  to  stimuli  in  anaerobic  organisms  is 
still  almost  nil  it  is  not  possible  at  present  to  ascertain  which 
component  in  the  metabolism  of  these  organisms,  adapted  to  life 
without  oxygen,  plays  an  analogous  role  to  that  of  the  oxydative 
in  aerobic  systems.  Our  investigations  must,  therefore,  be  re- 
stricted to  the  world  of  aerobic  organisms.  Here  we  have  seen 
that  the  different  stimuli  which  produce  an  excitating  effect  in- 
variably increase  the  oxydative  disintegration  of  the  living  system 
and  we  now  find  that  these  constituent  processes  of  metabolism 
likewise  form  a  point  from  which  depressing  responses  to  stimuli 
very  readily  proceed. 

The  prototype  of  this  group  of  processes  of  depression  in 
which  this  is  manifested  in  a  most  striking  manner,  is  that  of  a 
simple  asphyxiation  by  the  withdrawal  of  the  oxygen  supply 
from  the  exterior.  If  the  supply  of  oxygen  is  withheld  from  an 
aerobic  organism,  oxydative  disintegration  is  gradually  found  to 
be  more  and  more  decreased  and  further  breaking  down  takes 
place  a?ioxydatively,  as  oxydative  decomposition  forms  the  chief 
source  of  energy  production,  and  energy  production  consequently 
undergoes  a  gradual  decrease.  Excitating  stimuli,  therefore,  meet 
with  less  response  than  when  a  sufficient  supply  of  oxygen  is 
present,  that  is,  irritability  is  diminished.  As  a  result  of  this 
decrease,  a  corresponding  decrement  in  the  extension  of  excita- 
tion takes  place,  which,  in  turn,  is  likewise  manifested  by  the 


THE  PKOCRSSES  OF  DEPRKSSIOX  239 

restriction  of  the  perccptiljle  response  to  stinuilaiion.  In  the 
same  degree  in  whicli  oxydative  disintegration  l>cc(iines  less, 
o/zoxydative  breaking  down  i)r(»dncts  are  accunnilated.  The 
accumulation  of  these  products  likewise  plays  a  part  in  the  |)ro- 
duction  of  depression  and  increases  the  decrement  in  the  con- 
duction of  excitation.  1  he  decrease  of  cnerg)'  prfwluction  by 
decline  of  the  oxydative  dccomj)osition.  as  well  as  the  accumu- 
lation of  anoxydative  lireaking  down  products,  therefore,  simi- 
larly reduce  irritability  :  that  is,  their  effect  is  depressing.  This 
whole  series  of  processes,  which  we  have  previously  considered 
in  detail,  takes  place  on  the  withdrawal  of  (jxygen  and  leads  to 
the  dei)ression  of  asphyxiation.  It  can  readily  be  observed  in 
the  most  varied  kinds  of  aerobic  organisms  in  rhizo|)ods  and 
infusoria,  in  i)lant  and  ganglion  cells,  but  fmds  its  most  complete 
demonstration  in  the  nerves.  Here  these  jirocesses  can  l)c  easily 
produced  with  any  rapidity  desired,  accordingly  as  a  relative  or 
absolute  want  of  oxygen  is  brought  about.  These  same  typical 
results  are  likewise  shown  in  numerous  processes  in  which  the 
external  conditions  are  quite  diflerenl  in  nature. 

We  have  previously  become  accjuainted  with  such  a  ca.se  and 
studied  it  in  detail.  This  is  the  state  of  fatiijuc.  I^itiguc  is  a 
typical  state  of  depression,  that  is,  a  state  in  which  the  vital  pro- 
cess is  retarded  and  irritability  in  response  to  stinmli  corre- 
spondingly decreased.  Fatigue  is,  however.  a<  we  have  found. 
the  result  of  a  relative  deficiency  of  oxygen.  The  amount  of 
oxygen  at  disposal  is  not  sufficient  to  allow  of  disintegration, 
increased  by  constant  functional  activity  oxydatively  taking  place, 
to  develop  to  its  full  extent.  In  consecjuence  the  previously  cited 
sequence  of  processes  takes  ])lace.  A  "dej^ression  of  activity"  is 
produced.  Fatigue  is  true  asphyxiation  and  it  is  here  evident 
that  depression  proceeds  from  the  same  constituent  processes  of 
metabolism  as  excitation,  brought  about  by  a  single  .stimulus. 
Excitation  produced  by  constant  stinmli  gradually  merges  into 
depression  as  the  amount  of  oxygen  at  disposal,  even  if  augmented 
in  the  intact  organism  by  the  increa.sed  bUxKl  su|)|)ly.  for  instance, 
is  still  insufficient  to  meet  the  demand  made  by  the  increased 
oxygen  consumption  as  a    re.sult  of  continuous  functional  activity. 


240  IRRITABILITY 

A  further  very  interesting  example  of  depression  produced 
by  oxygen  deficiency  is  furnished  by  heat  depression.  It  has 
long  been  known  that  with  increasing  temperature  the  vital  mani- 
festations of  all  poikilothermic  organisms  at  first  undergo  a 
heightening  of  their  intensity.  If,  however,  after  a  maximum 
is  reached,  the  temperature  is  still  further  increased  a  sudden 
depression  sets  in.  The  increase  in  the  rapidity  of  the  vital  pro- 
cess as  a  result  of  increased  temperature  is  readily  understood 
when  based  on  the  well-known  law  discovered  by  van't  Hoff. 
Numerous  investigations  on  the  rapidity  of  the  course  of  special 
vital  manifestations,  as,  for  instance  the  growth  of  the  eggs  of 
the  frog  and  sea  urchin,  the  assimilation  of  carbon  dioxide  in 
green  plant  cells,  the  number  of  vacuole  pulsations  in  the  infu- 
soria cells,  the  frequency  of  the  heart  rate  of  the  frog  and  of  the 
mammal,  etc.,  have  shown  that  their  increase  does  in  fact  follow 
the  van't  Hoff  law,  being  doubled  or  tripled  in  amount  with  every 
increase  of  ten  degrees  of  temperature.  The  genesis  of  depres- 
sion produced  by  heat,  developed  in  different  organisms  at  various 
heights  of  temperature,  requires  a  closer  analysis.  This  depres- 
sion takes  place  at  temperatures  below  that  in  which  coagulation 
of  proteins  occurs.  Therefore,  under  certain  conditions,  with 
which  we  shall  presently  become  acquainted,  it  is  capable  of  being 
recovered  from,  whereas  in  higher  temperatures,  in  which  albu- 
men coagulates,  vital  activity  is  permanently  obliterated.  Depres- 
sion produced  by  heat  is,  therefore,  in  itself  not  a  necrobiotic 
process,  which,  as  such,  must  necessarily  lead  to  death.  But 
rather  like  fatigue  it  must  be  looked  upon  as  an  asphyxiation 
process.  Its  relations  to  oxygen  exchange  have  been  chiefly 
demonstrated  by  Winterstein^  by  his  investigations  on  the  central 
nervous  system  of  frogs  and  on  medusae.  He  found  that  when 
placed  in  a  heated  chamber  in  a  temperature  of  33-40°  the 
activity  and  reflex  excitability  of  the  frog  are  at  first  augmented. 
Within  the  lapse  of  a  short  time  this  increase  has  become  so 
great  that  the  slightest  touch  produces  tetanic  contractions,  simi- 

1  H.  Winterstein:  "Ueber  die  Wirkung  der  Warme  auf  den  Biotonus  der  Nerven- 
zentren."  Zeitschr.  f.  allgem.  Physiol.  Bd.  I,  1902.  The  same:  "Warmelahmung  tmd 
Narkose."     Ibid. 


THE  PROCESSKS  OE  DEPRESSION  241 

lar  to  tliosc  characteristic  oi  strychnine  innsoninj^.  \*cry  soon, 
however,  this  state  of  lii^Hi  excitation  is  followcil  by  one  of  de- 
pression, in  wliich  no  resjjonse  to  stinuih  can  be  obtained.  The 
animal  remains  entirely  motionless  in  any  position  in  which  it  is 
placed,  in  the  same  manner  as  a  froj^'  \vhn<e  nerve  centers  have 
been  completely  exhansted  by  strenuous  activity.  (  )n  the  !)asis  of 
our  knowledge  of  the  role  i)laye(l  by  the  deficiency  of  oxygen  in 
the  bringing  about  of  exhaustion  the  thought  arose,  if  in  this  heat 
depression  exhaustion  might  not  likewise  be  the  result  of  oxygen 
deficiency.  This  assumi)tion  ha--  been  most  strikingly  confinned 
by  the  investigations  of  W'intcrstcm.  li  has  been  demonstrated 
that  recovery  of  the  animal  in  a  slate  of  heat  dej)ression  cannot 
be  obtained  by  mere  cooling,  but  is  only  brought  alK>ut  when  at 
the  same  time  a  renewed  oxygen  supply  is  provided.  I**or  instance, 
a  frog  is  dei)ressed  in  the  warm  chamber  and  even  when  a 
strychnine  injection  has  been  introduced,  does  not  show  the 
slightest  reaction  to  stimuli.  In  the  warm  water  batli  artificial 
circulation  is  now  ap])lied  in  the  i)reviously  described  manner  with 
an  oxygen-free  saline  solution  at  'Mf  C,  so  that  tlic  blood  is  dis- 
placed and  thus  the  renewed  oxygen  sup])ly  to  the  nervous  centers 
prevented.  The  animal  can  now  be  cooled  and  the  warm  sahne 
solution  be  replaced  by  a  cooled  one  without  the  least  recovery 
taking  place.  If,  however,  blood  of  the  ox  with  contained  oxygen 
is  substituted  for  the  oxygen-free  saline  solution,  the  frog  shows 
signs  of  recovery  within  a  few  minutes  and  after  ten  or  fifteen 
minutes  responds  as  a  result  of  the  strychnine  to  the  merest  touch 
w'wh  tetanic  contractions  of  the  whole  body.  \\\  modifying  these 
methods  of  investigation  to  a  certain  extent  Houdy^  has  confimied 
these  results  to  the  fullest  extent.  Later  Wiiitrrstriu  by  quanti- 
tative determinations  of  oxygen  consumption  on  medusa*  showed 
that  at  30-35°  C,  at  which  temperature  heat  dei)ression  sets  in. 
the  consum])tion  of  oxygen  shows  an  increase  of  ab<»ut  tliree  and 
a  half  times  compared  to  that  in  a  temperature  of  11-12*  C. 
These  facts  show  that  we  have  in  heat  depression  a  prcK^ess  which. 
as  far  as  its  genesis  is  concerned.  i<  conipletelv  anal(»gous  to  tliat 

1  Oskar    Bondy:    "UntcrsuclnuiRcn    iihcr    dir    SanrrM..»Tauf»|»cichcrung    in    dco    Ner- 
vcnzentren."      Zeitschr.    f.   allpi-m.    Physiol.    R<J.    II.    1904. 


242  IRRITABILITY 

of  fatigue.  In  fatigue,  a  relative  want  of  oxygen  is  produced  by 
the  increased  consumption  following  functional  activity,  in  heat 
depression  by  the  increase  of  the  entire  metabolism  producing  a 
corresponding  increase  of  oxygen  requirement.  In  both  instances 
we  have  an  excitation  produced  by  external  stimuli  which  result 
in  an  increase  in  the  amount  of  oxygen  required,  and  in  both 
instances  the  oxygen  at  disposal  is  not  sufficient  to  permanently 
meet  the  augmented  demand.  In  both  types,  therefore,  decom- 
position must  become  more  and  more  anoxydative  and  the  well- 
known  series  of  processes  is  developed,  which  find  their  expres- 
sion in  depression. 

In  another  direction  likewise  heat  depression  is  of  special 
interest,  that  is,  in  regard  to  the  theory  of  nature  of  the  pro- 
cesses in  the  living  substance.  According  to  the  van't  Hoff  law 
we  may  assume  that  every  individual  constituent  metabolic  pro- 
cess, if  we  imagine  it  as  isolated  and  taking  place  in  a  test  tube, 
undergoes  in  more  or  less  the  same  degree  as  all  others  an  in- 
creased rapidity  of  reaction  as  a  result  of  increased  temperature. 
At  the  same  time,  in  living  substance  we  find  on  the  contrary 
that  the  van't  Hoff  law  is  only  within  certain  narrow  limits  more 
or  less  applicable  to  the  sum  total  of  all  metabolic  processes. 
Beyond  certain  degrees  of  temperature  no  further  increase  of 
the  vital  process  takes  place,  instead  a  retardation  occurs.  The 
analysis  of  depression  produced  by  heat  shows  us  in  the  clearest 
and  simplest  manner  the  reason  for  this  apparent  deviation  from 
the  general  law  of  van't  Hoff.  This  reasoning  is  based  on  the  fact 
that  the  rapidity  of  reaction  of  a  chemical  process  is  not  merely 
dependent  upon  the  temperature,  but  likewise  upon  the  mass 
relations  of  the  reacting  substances.  In  spite  of  the  effect  of  the 
temperature  in  increasing  the  rapidity  of  reactions,  the  process 
undergoes  retardation  which  extends  to  a  complete  cessation  if 
the  supply  of  material  necessary  to  its  existence  does  not  keep 
pace  with  the  increase  produced  by  temperature.  In  the  present 
instance  the  amount  of  reserve  supplies  for  the  building  up  of 
the  disintegrating  molecules  exists  in  abundance,  and  it  is  merely 
the  available  oxygen  which  is  in  relatively  a  very  small  quantity. 
As  soon,  however,  as  metabolism  in  its  entirety,  or  even  merely  in 


THE  PROCESSES  OE  DEPRESSION  243 

those  parts  in  wliicli  oxyj^aMi  is  directly  reciiiired,  is  increased  by 
whatever  means,  the  oxychitive  processes  would  l>c  the  first  to  fail 
and  it  must  be  from  tliis  point  that  tlie  disturbance  of  the  hamionv 
in  the  interacting^  of  tlie  in(h\  idual  metaboHc  processes  proceeds. 
This  principle  which  we  here  sec  manifested  in  its  simplest  ionw 
in  the  eftect  of  lemi)erature  on  oxyj^'en  exchange  in  the  f«)rm  of 
a  disturbance  in  the  correlations  of  the  individual  constituenl 
processes  based  on  an  alteration  of  the  mass  relation  and  the 
rapidity  of  reactions  of  individual  members  is,  lunvever,  not 
merely  restricted  to  elTects  of  temperature  and  the  results  quickly 
following  on  a  relative  oxygen  deficiency.  It  has,  indeed,  a  much 
more  general  significance  for  all  manner  of  constituent  nieta)>olic 
processes,  for  it  is  ai)plicable  to  all  nutrition  and  to  all  growth. 
and  forms  one  of  the  most  important  factors  which  intUience  the 
process  of  development,  that  is,  the  gradual  "metachronic"  altera- 
tions in  metabolism  to  wh.ich  all  living  systems  are  subjected  as 
long  as  life  endures. 

A  very  extensive  grouj)  of  depression  processes  is  produced 
by  the  action  of  chemical  stimuli,  .\mong  these  the  processes 
to  which  we  apply  the  collective  term  of  "narcosis"  must  claim 
our  special  interest.  As  is  well  known,  an  enormous  numlnrr  of 
substances  of  very  diflerent  chemical  nature.  sucJi  as  carl>on 
dioxide,  alcohol,  ether,  chloroform,  chloral  hydrate,  etc.,  exist. 
which,  possessing  the  ])roperty  of  i)roducing  cessation  of  the 
vital  activities  in  all  living  systems,  after  withdrawal  of  their 
application,  if  it  has  not  been  too  i)rol()nged  or  intense.  jK-nnit 
a  complete  restoration  to  normal  vitality.  These  are  the  tjcnrrai 
narcotics.  Besides  these  there  are  a  series  of  substances  which 
have  a  depressing  effect  only  ui)on  certain  forms  of  living  su!>- 
stance,  and  which  we  may,  therefore,  term  sf'ccial  narcotics.  As. 
however,  the  particular  nature  of  depression  following  the 
ai)plication  of  chemical  substances  has  hitherto  Uxn  closely 
studied  only  in  a  very  few  instances,  we  arc  not.  at  present,  in  a 
position  to  sharply  defme  the  limitations  of  the  conception  of 
narcosis,  a  conception  which  originally  had  hardly  any  further 
meaning  than  the  production  of  unconsciousness  by  chenncal 
means.      Tn    the    following   discussion,    therefore,    we   shall    d.--^! 


244  IRRITABILITY 

merely  with  narcosis  produced  by  the  well-known  general  nar- 
cotics, such  as  carbon  dioxide,  alcohol,  ether,  chloroform,  etc. 
From  the  time  of  the  introduction  of  ether  narcosis  into  medical 
practice  by  Jackson  and  Morton  in  the  year  1848  up  to  the  present 
day,  the  theory  of  this  process  has  awakened  the  liveliest  interest. 
Many  attempts  have  since  been  made  to  explain  the  physical 
nature  of  this  interesting  process  without,  however,  any  generally 
acknowledged  theory  of  narcosis  being  established.  I  will  refrain 
from  entering  into  these  former  theories  in  detail  as  they  have 
been  exhaustively  treated  by  Overton^  in  his  studies  on  narcosis. 

In  connection  with  our  present  observations,  however,  I  will 
more  closely  analyze  the  process  itself,  following  the  results  of 
investigations  extending  over  more  than  ten  years  carried  out  by 
my  coworkers  and  myself.  In  these  investigations  it  has  been 
found  that  narcosis  belongs  to  this  group  of  depressing  processes. 
A  satisfactory  theory  of  narcosis,  however,  and  this  I  must  ex- 
plain from  the  first,  can  even  today  not  be  arrived  at.  Such  a 
theory  would  require  the  ascertainment  of  all  primary  and  sec- 
ondary alterations  produced  by  the  narcotic  in  the  course  of  nor- 
mal vital  activity.  For  this,  however,  a  number  of  minute  details 
are  still  lacking.  Nevertheless,  the  careful  and  detailed  investiga- 
tions during  the  last  ten  years  have  acquainted  us  with  a  large 
number  of  alterations,  which,  acting  as  conditioning  factors  for 
the  process  of  narcosis,  must  be  taken  into  consideration,  and 
which  to  a  certain  extent  give  us  an  idea  of  the  mechanism  of  this 
process.  They  are  equally  interesting  from  a  theoretical  as  well 
as  from  a  practical  point  of  view.  The  presentation  will  become 
more  detailed  as  more  of  such  conditioning  factors  are  established 
by  the  deeper  penetrating  of  future  analysis.  I  will  deal  here  with 
the  facts  found  up  to  the  present  and  then  proceed  to  the  deduc- 
tions which  these  furnish  for  the  theory  of  narcosis. 

In  the  first  place  narcosis  is  stamped  as  a  typical  process  of 
depression,  being  characterized  by  a  decrease  of  irritability  zvith 
a  corresponding  decrement  of  the  extent  of  excitation.  The  chief 
feature  of  all  narcotized  systems  is,  that  in  slight  narcosis  exci- 

\  E,  Overton:  "Studien  iiber  die  Narkose,  zugleich  ein  Beitrag  zur  allgemeinen 
Pharmakologie."     Jena   1901. 


TIIF.  PRDCKSSES  OF  DEPRESSION'  245 

tating  stimuli  produce  a  greatly  weakened  excitation,  and  that 
in  deep  narcosis  no  ])ercei)til)lc  response  is  obtained.  This  can 
readily  be  ascertained  in  the  various  forms  of  living  substance. 
According  to  the  previous  observations  on  the  inseparable  rela- 
tions between  conduction  of  excitation  and  irritability,  it  is  self- 
evident  that  with  decrease  of  irritability  there  must  Ik?  a  corre- 
sponding decrease  in  the  cai)ability  of  the  conduction  of  excita- 
tion from  the  ])oint  of  stimulation.  This  decrease  in  conduc- 
tivity must,  therefore,  be  the  greater  the  more  irritability  is  re- 
duced ;  that  is,  the  deeper  the  narcosis,  the  greater  must  1)C  the 
decrement  undergone  by  the  wave  of  excitation  in  its  extension 
from  the  point  of  stimulation.  These  facts  can  \)c  obser\'cd  in 
the  highest  perfection  in  the  nerve,  and  have,  as  we  have  seen, 
been  demonstrated  by  the  investigations  of  ll'critjo.  Dcndrinos, 
Noll,  Boruttau  and  Frohlicli.^  V\H)n  deei)er  analysis  of  this  pro- 
cess of  depression,  the  next  task  for  the  investigator  nuist  !)c  the 
ascertainment  of  the  special  components  of  the  metabolic  activity, 
which  are  depressed  as  a  result  of  the  narcotic. 

As  a  consequence  of  the  result  of  my  investigations  on  fatigue, 
the  idea  occurred  to  me  to  test  if  possibly  oxygen  exchange  like- 
wise undergoes  depression  during  narcosis.  The  sj>inal  cord 
centers  of  the  frog,  which  had  served  me  in  ascertaining  the  role 
played  by  oxygen  in  the  Ijringing  about  of  the  depression  of 
activity,  appeared  likewise  a  favorable  object  for  this  investi- 
gation. Indeed,  the  cjuestion  if  consumjjtion  of  oxygen  takes 
place  during  narcosis,  could  be  experimentally  deiermined  in 
direct  connection  with  the  investigations  on  fatigue.  This  was 
based  on  the  following  consideration.  If  an  oxygen-free  saline 
solution  is  introduced  into  the  aorta  of  a  frog  and  in  order  to 
increase  the  activity  of  the  si)inal  cord  centers  to  the  maximum 
the  animal  is  poisoned  with  strychnine,  after  a  very  short  time 
complete  exhaustion  takes  place  as  a  result  of  oxygen  deficiency. 
This  exhaustion  can  only  be  removed  by  the  introduction  of 
oxygen.     In  this  condition  the  oxygen  recjuirement  of  the  centers 

1  I  have  previously  on  another  occasion  briefly  communtcaled  the  * 

from  the  investigations  ma<le  at  the  Cottinffcn   1:'    -    •    ■      '■    tiv  c<>«  ; 

C(.mpare:    Max    /  VrTi^-rn  .•  "Ucbcr    Narkosr."      1  >  m.   W.  t.    1909. 


246  IRRITABILITY 

is  enormously  increased.  If  the  centers  are  narcotized  by  adding 
a  narcotic  to  the  oxygen-free  circulating  fluid  in  amounts  which, 
as  experience  has  found,  would  produce  complete  loss  of  reaction 
in  the  normal  animal,  for  example,  about  5  per  cent,  of  alcohol, 
it  can  then  be  tested  if,  in  this  state  of  narcosis,  the  centers  are 
capable  of  oxygen  consumption.  It  is  merely  necessary  to  re- 
place the  oxygen-free  saline  solution  containing  alcohol  by  blood 
rich  in  oxygen,  containing  alcohol  in  an  amount  sufficient  to  con- 
tinue the  narcosis,  but  supplying  an  abundance  of  oxygen.  If, 
after  this  artificial  circulation  has  lasted  for  a  sufficient  period, 
the  blood  is  then  displaced  by  an  oxygen-free  saline  solution 
containing  alcohol,  and  then  this,  in  turn,  is  replaced  by  an 
oxygen-  and  alcohol-free  saline  solution,  so  that  cessation  of  the 
narcosis  is  now  produced,  it  can  be  ascertained  by  the  responses 
of  the  animal  if  consumption  of  the  oxygen,  when  at  the  dis- 
posal of  the  centers  during  narcosis,  has  taken  place  or  not.  If 
the  former  is  the  case,  then  on  the  cessation  of  narcosis  reflex 
contraction  must  occur  in  the  same  manner  as  in  every  strych- 
ninized  frog  totally  exhausted  by  oxygen  deficiency  and  into 
which  a  saline  solution  containing  oxygen  is  reintroduced.  If 
during  narcosis,  on  the  other  hand,  oxygen  has  not  been  con- 
sumed by  the  centers,  depression  must  continue  to  be  present 
after  cessation  of  narcosis.  Testing  the  recovery  of  the  animal 
on  the  introduction  of  blood,  rich  in  oxygen,  serves  as  an  indi- 
cator for  the  vital  activity  and  capability  of  recovery  of  the 
centers.  A  great  number  of  experiments  based  on  this  scheme 
of  investigation  were  undertaken  at  my  request  by  Winterstein} 
These  were  carried  out  with  alcohol,  ether,  chloroform  and  also 
carbon  dioxide.  His  experiments  have  shown  in  the  most 
uniform  manner  that,  in  spite  of  the  requirement  of  oxygen  by 
the  centers  being  increased  to  its  highest  extent,  and  notwith- 
standing the  most  ample  oxygen  supply  during  narcosis,  after 
cessation  of  the  same  and  the  introduction  of  an  oxygen-free 
saline  solution  no  trace  of  recovery  occurred,  whereas  after  a 
supply  of  oxygen  was  introduced  tetanic  contractions  reappeared 

\  H.    Winterstein:    "Zur    Kenntniss   der    Narkose."      Zeitschr.    fur   allgem.    Physiol. 
Bd.   I,   1902. 


THE  PROCESSES  OE  DEPRESSION  247 

at  once.  During  narcosis,  therefore,  the  centers,  in  spxte  of  thcxr 
great  requirement  of  oxygen,  lose  their  capability  of  oxydative 
splitting  up  and  consumption  of  oxygen. 

After  tile  nielliods  for  aspliyxialion  of  ihc  nene  had  U-cn 
worked  out  and  perfected  the  wi^li  arose  Hkewisc  to  carry  out 
for  these  structures  an  analo^'ous  scries  of  experiments  to  that 
employed  for  llic  centers  and  based  on  the  same  chain  of  reason- 
ing. These  investigations  have  the  advantage  of  essentially 
simpler  conditions.  After  having  convinced  myself  l)y  exixrri- 
ments,  that  the  results  on  the  nerve  were  in  coini)lcte  conformity 
with  those  on  the  spinal  cord,  at  my  suggestion  I-rohlich'  re|H'aled 
and  continued  these  experiments  on  a  more  extended  scdlc. 
A  nerve  was  asphyxiated  by  the  previously  described  method. 
This  is  accomplished  in  the  simijlcst  manner  by  the  ojH:ning 
or  closing  of  stop  cocks  in  the  api)aratus  I  have  employc<l 
which  permit  of  pure  nitrogen,  or  nitrogen  witli  ether,  and  tiiially 
also  oxygen  with  ether  or  ])ure  oxygen  !)cing  conducted  at  will 
through  the  glass  chamber.  If  the  nerve  was  so  far  depres.scd 
in  pure  nitrogen  that  conductivity  became  obliterated  for  alK)Ut 
two  cm.  of  the  asi)hyxiated  stretch,  it  was  then  narcotized  in 
nitrogen.  Following  this  oxygen  with  ether  was  supj)licd  for  a 
time.  Then  the  oxygen-ether  mixture  was  displaced  by  one  of 
nitrogen  and  ether  and  finally  by  pure  nitrogen.  I-!ven  after  a 
prolonged  period,  a  recovery  in  pure  nitrogen  never  took  place. 
On  the  other  hand,  the  nerve  recovered  at  once,  as  soon  as  oxygen 
without  ether  was  introduced.  Tlic  results  of  these  investigations 
are,  therefore,  com])letely  in  harmony  with  those  undertaken  by 
Winterstein  on  the  nervous  centers.  They  were  later  likewise 
entirely  confirmed  by  similar  exj)eriments  of  Ueaton.'  .\\\  these 
investigations  furnished  the  proof  ///(//  in  narcosis,  living  sub- 
stance, not7vithstandi)ig  eroi  the  greatest  oxygen  deficiency,  is 
not  capable  of  producing  oxydation,  neither  can  consumption  of 
oxygen  take  place,  ivith  ivhich.  after  cessation  of  the  luirrntix, 
oxydative  splitting  up  can  be  carried  out. 


1  Fr.   IV.  Frohlich:  "Zur  Kenntniss  dcr  Narkosc  de«  Nervcn."     Zcil»chr.   f.  all| 
Physiol.    Bd.    Ill,    1904. 

2  Trevor  B.   Hcaton:  "Zur   Kenntniss  dcr   Narko»«r."     Zritschr.    f.   allgrm.    PhftioL 

Bo.   1910. 


248  IRRITABILITY 

Recently  Warburg'^  has  likewise  found  an  oxydative  depression 
during  narcosis  in  the  eggs  of  the  sea  urchin  and  in  the  red  cor- 
puscles of  geese,  and  the  same  fact  has  lately  been  also  demon- 
strated by  Joannovics  und  Pick-  for  the  oxydative  activity  of  the 
liver  cells  of  the  dog. 

This  fundamental  establishment  of  the  fact  that  narcosis  pre- 
vents oxydations  in  living  substance  is  at  once  followed  by  the 
further  problem,  in  what  manner  do  the  disintegration  processes 
undergo  alterations  during  narcosis?  That  they  must  be  altered, 
and  this  in  the  form  of  a  reduced  energy  production,  is  clearly 
shown  by  the  decrease  of  irritability  and  the  increase  of  the 
decrement  of  the  conduction  of  excitation.  Both  become  the 
greater  the  deeper  the  narcosis.  The  observations  just  discussed 
render  these  facts  at  once  self-evident.  They  follow  as  a  simple 
and  necessary  result  of  the  elimination  of  the  oxydative  pro- 
cesses. If  these  are  suppressed  further  breaking  down,  if  not 
influenced  by  addition  of  other  factors,  proceeds  anoxydatively. 
The  previously  observed  series  of  processes  is  developed,  which 
invariably  take  place  when  oxygen  deficiency  occurs  and  which 
produce  in  the  clearest  form  the  results  of  asphyxiation  on  the 
withdrawal  of  oxygen  supply.  If,  therefore,  the  disintegration 
processes  are  not  influenced  in  some  other  manner  during  nar- 
cosis, they  must  then  take  place  in  the  same  way  as  in  the  with- 
drawal of  the  oxygen  supply.  The  question,  if  this  is  actually  the 
case,  can  be  experimentally  decided  by  comparing,  on  the  one 
hand,  the  development  of  the  course  of  asphyxiation  during  nar- 
cosis, and  on  the  other,  the  withdrawal  of  the  oxygen  supply. 
We  have  carried  out  this  comparison  for  the  spinal  cord  centers 
as  well  as  for  the  medullated  nerve.  A  prolonged  series  of  exper- 
iments have  been  made  by  Bondy^  with  the  apparatus  constructed 

1  Otto  Warburg:  "Ueber  die  Oxydationen  in  lebenden  Zellen."  Zeitschr.  f. 
physiol.  Chemie  Bd.  66,  1910.  The  same:  "Ueber  Beeinflussung  der  Oxydationen  in 
lebenden  Zellen  nach  Versuchen  an  roten  Blutkorperchen."  Zeitschr.  f.  physiol. 
Chemie  Bd.  69,  1910. 

2  Joannovics  und  Pick:  "Intravitale  Oxydationshemmung  in  der  Leber  durch  Nar- 
kotica."     Pfliigers  Arch.  Bd.   140,   1911. 

3  Bondy:  "Untersuchungen  iiber  die  Sauerstoffspeicherung  in  den  Nervencentren." 
Zeitschr.   f.   allgem.    Physiol.    Bd.   Ill,    1904. 


THE  PROCESSES  OF  DEPRESSION  249 

for  this  puri)ose  l)y  Haijlioni:  Two  frojrs  iiiidcr  uinlorm  comli- 
tions  of  temperature  were  sul)niiite<i  to  artificial  circulation,  the 
one  merely  witli  an  oxyj^en-frec  fluid,  the  other  with  the  same. 
but  with  the  addition  of  .")  j)er  cent,  of  alcohol.  In  order  to  render 
the  least  trace  of  irritability  |)erce|)tible,  resi>onsivily  was  in- 
creased in  jjoth  animals  by  the  employment  of  strychnine.  It 
then  appeared  that,  on  the  averap^e.  irritability  was  obliterated  \\\ 
the  narcotized  frog  in  about  the  same  time  as  in  the  animal 
simi)ly  asphyxiated.  These  experiments  were  controlled  bv  intro- 
ducing  at  tlieir  conclusion  a  saline  solution  containing  oxygen 
into  both  frogs  and  by  ascertaining  the  degree  of  recovery.  In 
like  manner  Frohliclr  has  established  the  same  fact  for  the  nerve. 
The  period  of  asi)hyxiation  for  the  nerve  in  a  nitrogen-ether 
mixture  is  approximately  the  same  as  in  pure  nitrogen.  Analo- 
gous exi)criments  have  been  carried  out  in  am<eb.'c  by  Ishika'ca^ 
Here  also  it  has  been  shown  that  living  substance  l)ecomes 
asphyxiated  in  narcosis  and  can  hnally  recover  only  when  oxygen 
is  supplied.  In  more  than  a  hundred  exi)eriments  Ishikan'a  has, 
however,  obtained  the  uniform  rouit  tliat  anurba?  asphyxiate 
rather  sooner  in  narcosis  than  in  i)ure  nitrogen.  The  most  strik- 
ing experiments  are  those  which  Hcatoti*  has  carried  out  on  the 
nerve.  Using  both  sciatic  nerves  of  the  same  frog,  he  passed 
each  one  through  a  separate  glass  chamber,  as  previously  <ie- 
scribed,  and  laid  the  central  stumi)s  projecting  from  the  chanil>cr 
over  a  pair  of  platinum  electrodes,  while  the  stretch  within  was 
likewdse  placed  on  platinum  electrodes.  The  nniscles  served  as 
indicator  of  the  capability  of  conduction  and  irritability.  The 
alterations  thereof  were  tested  by  the  ascertainment  of  the 
threshold  of  stimulation.  The  nerve  in  the  one  chaml>er  was 
then  subjected  to  a  pure  nitrogen  current,  that  in  the  otlwr  merely 
to  one  of  pure  air  with  ether,     in  order  to  test  the  degree  of 

1  Baglioni:   "Bczichungcnzwislicn    physiolonisclicr    Wirkung   und   chcmi»<:hcr    Conui 
tution."     Zeitschr.   f.   allgcm.    Physiologic   Bd.    III.    1904. 

2  Fr.    ll\   Frohlich:  "Zur   Kcnntniss  dcr   Narko»c  dc»  Nervcn."     Zeitschr.   f.  lilffrm. 
Physiologic  B<1.    III.    l'>04. 

3  The  experiments  of  Ishikaua  have  not  as  yet   been   pii' '    " 

4  Trevors  B.   Hcaton:  "7.ut    Kcnntniss  dcr   Narkosc."      /.  <■     *tl*fm     Phirwol- 
ogie   Bd.   X,    1910. 


250  IRRITABILITY 

asphyxiation  the  air-ether  current  in  the  latter  chamber  was 
replaced  from  time  to  time  by  an  ether-nitrogen  current,  and 
then  by  one  of  pure  nitrogen,  so  that  the  narcosis  was  interrupted 
without  the  entrance  of  oxygen  being  possible  in  the  mean  time. 
During  this  suspension  of  the  narcosis,  the  nerve  recovered  each 
time  in  nitrogen,  its  irritability  again  increasing  and  its  capa- 
bility of  conduction  returning  with  every  test.  However,  re- 
covery showed  itself  as  less  and  less  complete.  Finally  irrita- 
bility had  sunk  so  low  that  the  capability  of  conduction  disap- 
peared entirely.  At  the  end  of  the  experiment  as  control,  nitro- 
gen was  displaced  by  air  in  the  two  chambers  and  in  both  nerves 
recovery  took  place. 

In  both  cases  recovery  could  only  be  brought  about  by  an  intro- 
duction of  oxygen.  From  the  sum  of  all  these  experiments  it 
results  that  during  narcosis  in  air  the  nerve,  even  when  a  suffi- 
ciency of  oxygen  is  present,  gradually  asphyxiates  and  loses 
its  capability  of  conduction,  and  this  in  about  the  same  length 
of  time  as  the  other  nerve  in  pure  nitrogen.  These  investiga- 
tions furnish  two  important  facts  for  the  theory  of  narcosis. 
First,  that  in  narcosis  living  substance  becomes  asphyxiated  not- 
withstanding the  presence  of  an  ample  oxygen  supply,  and 
secondly,  that  asphyxiation  occurs  in  the  same  time,  or  some- 
what more  rapidly,  in  pure  nitrogen  under  otherwise  similar 
conditions  than  without  narcosis.  In  other  words,  it  is  shown 
that  the  breaking  down  processes  of  metabolism  continue  in  nar- 
cosis as  anoxydative  disintegration.  In  narcosis,  therefore, 
asphyxiation  takes  place  zvith  approximately  the  same  or  a  some- 
what greater  rapidity  than  that  in  an  oxygen-free  medium. 

The  fact  here  established  explains  in  the  simplest  manner  the 
often  described  observation  that  in  the  human  being  and  in  mam- 
mals during  prolonged  anaesthesia  typical  products  of  insufficient 
combustion,  such  as  fatty  acids,  lactic  acid  and  above  all  aceton, 
in  not  inconsiderable  quantities  are  eliminated,  as  the  case  may 
be,  by  the  urine  or  the  respiratory  air.^    If,  as  has  been  shown  by 

1  For  the  very  extensive  literature  on  this  subject  see  Reicher:  "Chemisch- 
experimentelle  Studien  zur  Kenntniss  der  Narkose."  Zeitschr.  f.  klinische  Medicin 
Bd.   65,    1908. 


THE  PROCESSES  OF  DEPRESSION  251 

the  foregoing  experiineiits,  tlic  f)rocesses  of  disintegration  can 
continue  to  anoxydatively  take  place  during  narcosis,  the  prob- 
lem arises,  if  this  anoxydative  l)reaking  down  can  be  further 
increased  by  excitating  stimuli.  This  question  has  been  answered 
likewise  by  means  of  exj)eriments  on  the  nerve  made  by  Heaton,* 
The  two  sciatic  nerves  of  the  same  frr>g  were  drawn  through 
a  double  glass  chamber  of  the  f(jrm  i)rcvi()Usly  dc^cril)cd  so  that 
each  nerve  lay  on  an  electrode  and  with  the  central  stump  pro- 
truding out  of  the  chamber  hanging  likewise  over  an  clectro<le. 
As  in  the  former  instances  the  muscle  contraction  of  the  shank 
again  served  as  indicator.  I'.oth  nerve-^  were  then  subjected  to 
the  same  current  of  nitrogen-ether.  When,  as  a  result  of  the 
narcosis,  their  irritability  has  sunk  to  the  level  of  "stromschleifen" 
the  central  stunij)  of  the  one  nerve  was  continuously  stimulated 
with  faradic  shocks  during  a  prolonged  period,  while  the  other 
nerve  remained  at  rest,  h'inally.  by  displacement  of  the  current 
of  nitrogen-ether  with  one  of  pure  nitrogen,  cessation  of  narcosis 
was  brought  about.  It  was  then  seen  that  the  irritability  of  the 
continuously  stimulated  nerve  showed  a  nuich  greater  decrease 
than  that  of  the  nonstimulated.  The  control  made  by  introiluc- 
tion  of  air  demonstrated  that  both  nerves  recovered  in  an  oxygen 
supply.  There  ca)i,  therefore,  be  no  doubt,  by  comparative  exper- 
iments zve  find,  that  durinq  narcosis  anoxydatirc  disintegration 
can  be  still  further  i)icreased  by  the  action  of  stimuli. 

In  view  of  this  knowledge  of  the  intbicncc  of  narcotics  on 
oxygen  exchange  it  nia\  be  considered  as  a  tirmly  established 
fact,  that  a  process  of  dej^ression  is  developed  during  narcosis, 
which  can  be  classified  with  the  large  group  of  depressions,  re- 
sulting from  deficiency  of  oxygen.  This  is  followed  by  the  imix^r- 
tant  problem,  is  it  possible  to  attribute  the  whole  scries  of  altera- 
tions, produced  by  the  narcotic,  solely  to  this  one  factor?  In  other 
words,  is  narcosis  the  result  of  acute  suppression  of  the  oxyda- 

tive  processes? 

If  the  individual  .symptoms  which  characterize  narcosis  are 
investigated  from  this  point  of  view,  one  must  indeed  confess 
that  they  are  all  readily  understood  when  regarded  as  the  results 

1  Heaton  :  1.  c. 


252  IRRITABILITY 

of  suppression  of  the  oxydative  processes.  Indeed,  the  disap- 
pearance of  the  perceptible  vital  activities,  the  decrease  of 
irritability,  the  restriction  of  the  conduction  of  excitation,  the  con- 
tinuance of  an  anoxydative  breaking  down,  the  recovery  on  ces- 
sation of  narcosis,  provided  oxygen  is  present,  etc.,  in  short,  all 
the  characteristics  of  narcosis  so  far  known  must  be  expected 
and  demanded  if  a  suppression  of  the  oxydative  processes  exists 
during  narcosis. 

There  is  only  one  point  which  at  the  first  glance  would  not 
seem  to  agree  entirely  with  the  assumption.  This  is  the  fact  that 
depression  sets  in  with  a  relatively  greater  rapidity  in  narcosis 
than  when  the  supply  of  oxygen  is  completely  withdrawn. 
Depression  of  the  centers  in  the  spinal  cord,  which  begins  in 
about  five  to  ten  minutes  after  artificial  circulation  of  an  oxygen- 
free,  alcohol-containing,  saline  solution,  is  not  brought  about  for 
more  than  an  hour  when  the  same  saline  solution  but  without 
alcohol  is  introduced.  This  difference  is  still  more  strikingly 
apparent  in  the  nerve.  The  same  degree  of  depression,  which  is 
produced  in  the  nerve  in  a  nitrogen-ether  mixture  within  about 
five  minutes,  is  not  reached  in  pure  nitrogen  without  ether  until 
after  the  lapse  of  from  two  to  four  hours.  In  order  to  investi- 
gate this  relation  somewhat  more  closely  I  have  questioned  if  it 
is  possible  for  a  living  system,  which  has  been  narcotized  to  a 
certain  extent,  to  regain  its  irritability  in  a  completely  oxygen- 
free  medium,  if  cessation  of  the  narcosis  takes  place  after  a 
period  essentially  shorter  than  the  time  of  asphyxiation  of  the 
system  under  equal  conditions.  If  the  depression  of  narcosis  is 
founded  exclusively  on  asphyxiation,  it  would  be  expected  that 
no  recovery  could  occur.  Experiments  which  I  have  made  on 
the  spinal  cord  centers  as  well  as  on  the  peripheral  nerves  have, 
however,  demonstrated  exactly  the  contrary.  If  a  frog  is 
subjected  to  an  artificial  circulation  of  an  oxygen-free  saline 
solution  containing  5  per  cent,  of  alcohol  until  reaction  is  lost, 
being  certain  of  this  by  the  injection  of  a  weak  dose  of  strych- 
nine, and  if  now  a  cessation  of  the  narcosis  is  brought  about  by 
the  transfusion  of  oxygen-free  saline  solution,  the  centers  of  the 
animal  recover  completely  within  ten  to  fifteen  minutes,  as  shown 


Till-:  PROCESSES  OI-   DI-PRESSION  ::o.i 

by  typical  strycliniiK-  tetanus.  If  a  nerve  is  f)lacc(l  in  a  gas  cham- 
ber throivc:b  which  a  mixture  of  nitroj^'cn  and  ether  is  allowed  to 
flow  until  irritability  is  ^^reatly  decreased,  and  is  then  displaced 
by  pure  nitro^^en.  irritability  increases  more  or  less  completely 
according  to  the  time  which  has  passed  from  the  !>eginning  of 
asphyxiation.  This  investigation  proves  that  living  substance, 
even  after  the  (leei)est  narcotic  depression,  may  recover  on  ces- 
sation of  the  narcosis,  although  in  an  entirely  oxygen- free  medium. 
Frohlich,  Botidy  and  Heat  on,  by  the  methods  of  their  ex|)cri- 
ments  above  described,  have  |)roved  this  fact  in  a  great  numU-r 
of  instances.  On  the  other  hand.  Ishikaica  could  not  obscn'C 
a  pronounced  recovery  in  ani<eb.'e  from  narcosis  in  pure  nitrogen. 
But  it  is  possible  that  here  the  difference  is  |)crhaps  merely 
quantitative. 

What  position  should  be  taken  in  the  face  of  these  facts?  Docs 
recovery  of  a  deeply  narcotized  tissue  in  an  oxygen-free  medium 
really  make  it  difficult  to  suppose  that  narcosis  is  the  result  of 
an  acute  suppression  of  the  processes  of  oxydation?  r)n  closer 
view,  it  will  be  found  that  this  difViculty  is  merely  apj)arent.  In 
reality  it  is  quite  possible  to  bring  these  facts  into  harmony  with 
the  assumption  that  narcosis  consists  in  a  suj)|)ression  of  these 
processes.  If  one  proceeds  from  the  sui)position  that  living  sub- 
stance possesses  a  certain,  even  though  merely  a  small  supply  of 
oxygen  in  its  interior,  then  it  is  at  once  evident  that  a  more  or 
less  complete  recovery  of  irritability  from  narcosis  depression  is 
possible,  even  in  an  oxygen- free  medium.  It  can  take  place  at 
the  cost  of  the  oxygen  still  present  in  the  living  substance  and 
which  during  the  narcosis,  on  account  of  the  sui)pression  of  the 
oxydation  processes,  could  not  be  consumed.  If  the  presence  of 
a  certain  oxygen  reserve  in  living  substance  is  entirely  set  aside 
and  a  different  explanation  sought  for  the  i»rimary  continuance 
of  irritability  after  a  complete  withdrawal  of  the  oxygen  supply 
from  without,  the  great  difference  of  time  in  the  setting  in  of  the 
depression  in  narcosis  and  that  of  the  comj^lete  elimination  of  the 
oxygen  supi)ly  from  without  would  make  it  necessary  to  assume 
the  processes  occurring  in  narcosis  are  entirely  <lifferent  in  nature. 
The  explanation  that  narcosis  is  the  result  of  sui>i>ression  of  the 


354  IRRITABILITY 

oxydative  processes  would  indeed  be  out  of  the  question  in  such 
a  view. 

The  assumption,  however,  that  in  a  living  system  at  the  same 
moment  when  oxygen  is  removed  from  the  neighborhood,  let  us 
say  by  a  stream  of  nitrogen,  no  oxygen  would  be  present  and 
that  in  consequence  every  oxydative  process  must  cease,  contains 
so  little  probability  that  I  have  rejected  it  on  various  occasions.^ 
The  way  in  which  irritability  is  lost  in  asphyxiation  of  the  nerve 
likewise  very  clearly  demonstrates  the  untenability  of  this  view. 
The  recent  investigations  of  Lodholz-  have  shown  that  decrease  of 
irritability  takes  place  after  a  sudden  displacement  of  all  oxygen 
from  the  surrounding  medium  uniformly  and  gradually  in  the 
form  of  a  logarithmic  curve.  If  at  the  moment  of  oxygen  with- 
drawal from  the  outer  medium,  metabolism  became  entirely 
anoxydative,  the  curve  of  irritability  must  under  all  circumstances 
show  a  sudden  steep  decline  at  this  point,  and  subsequent  to  this 
a  further  slower  decrease.  For,  as  the  oxydative  processes  con- 
stitute by  far  the  chief  part  in  the  energy  production  of  living 
substance,  the  production  of  energy,  and  with  this  irritability, 
would  undergo  considerable  loss  at  the  same  moment  in  which 
oxydative  was  replaced  by  anoxydative  disintegration.  The  curve 
of  decrease  of  irritability  during  the  transition  period  from 
oxygen  supply  to  oxygen  withdrawal  shows,  on  the  contrary,  a 
completely  uniform  course  and  it  is  not  until  later  that  a  very 
slow  decline  takes  place,  which  only  after  a  prolonged  time  as- 
sumes increasing  rapidity.  But  the  assumption  that  at  the 
moment  when  the  supply  of  oxygen  ceases,  anoxydative  breaking 
down  could  acquire  such  enormous  dimensions  that  it  furnishes 
just  exactly  the  same  amount  of  energy  as  was  before  supplied 
oxydatively,  is  a  view  which  no  one  will  seriously  entertain.  In 
connection  with  this  I  wish  to  call  attention  to  the  experiments 
of  Frohlich^  in  which  he  compared  the  time  required  for  asphyx- 
iation to  take  place  in  the  nerves,  when,  on  the  one  hand,  the  frogs 
had  been  kept  several  days  previous  to  the  experiment  in  tempera- 

1  Compare  lecture  V;  lecture  VII. 

2  The  investigations  have  not  yet  been  published. 

ZFr.    W.    Frohlich:   "Das    Sauerstofifbediirfniss   des    Nerven."      Zeitschr.    f.    allgem. 
Physiol.  Bd.  Ill,  1904. 


THE  PROCESSES  OF  DEPKi:SSK)N 


'^ob 


tiire  of  14-40°  C,  and  on  the  otlicr.  in  one  merely  a  few  degrees 
above  zero,  lie  found  tliat  llie  nerves  of  the  cooled  froffs  re- 
quired on  an  averaj^'e  twice  or  three  times  as  long  for  their  irri- 
tability to  sink  to  tlie  same  degree  as  those  of  the  heated  frog. 
although  (hiring  the  experiment  the  same  tem|K-rature  was  pre 
in  both.  It  was  also  sliown  tliat  the  aspliyxiation  |)eri<Ml  was  pro- 
longed up  to  a  certain  limit,  depending  uj>on  the  length  of  time  the 
animals  were  kept  at  a  low  temperature.  It  would  seem  to  me 
that  these  facts  admit  of  no  other  explanation  than  that  in  a  low 
temperature  a  greater  amount  of  oxygen  is  stored  in  the  ner>'e 
than  in  high  temperatures.  hVom  the  standf)oint  that  from  the 
monient  of  withdrawal  of  oxygen  from  without,  disintegration 
likewise  takes  place  exclusivelv  anoxvdalivelv,  these  facts  would 
be  completely  incomprehensible.  When,  however,  the  assum|>- 
tion  is  made,  and  this  would  ai)i)ear  to  me  as  inevitable,  that  living 
substance  contains  in  itself  a  certain  even  though  a  very  sligfii 
quantity  of  oxygen,  which  in  low  tcmi)erature  is  greater,  in  a 
high  temperature  less,  the  recovery  from  narcosis,  when  oxygen 
is  withheld,  is  not  at  all  surprising.  The  comparatively  rapi<l 
setting  in  of  depression  in  narcosis  finds  a  simple  explanation  in 
the  violent  manner  in  which  the  oxydative  breaking  down,  not- 
withstanding the  presence  of  oxygen,  is  suddenly  suppressed  by 
the  flooding  by  the  narcotic.  Finally,  this  view  receives  unl«M»ke<l- 
for  support  by  a  group  of  facts  which  at  the  first  glance  would 
appear  to  bear  no  relation  whatever  to  the  j)rtKess  of  narcosis. 

In  a  series  of  investigations  on  the  mechanism  of  movement  in 
naked  protoplasm,^  I  have  pointed  out  the  role  played  by  oxygen 
in  the  genesis  of  the  aiiKxhoid  protoplasm  movement.  We  can 
distinguish  two  antagonistic  i)hases  in  the  movement  of  am^rlioid 
cells,  the  expansion  phase  and  the  contraction  phase.  The  first 
consists  in  an  increase,  the  latter  in  a  diminution  of  the  surf 
the  mass  remaining  the  same.    The  expansion  phase  is  manifesie<i 

\  Max    Verworn:   "Die    physiologische    Bcdcutimic   dc»    Zcllkeruk."      Itlu*rf»    Aich. 

Bd.    51.    1891. 

The    same:    "Hie    BcweguiiR   dcr    IcbendiRcn    Sul.»lan».      Fine    vcrtlrifhrod  i4ir«<»»<>- 
gische  Untersuchur.R  dcr  Contraction»cr»chcinungcn."     Jena   1892. 

The    same:    ".Mlgemeinc    Physiologic."      V    AnflaKc.      Jena    1909.      In   V - 
the  same  theory  of  the  contraction  movements  with  •ome  new  corrro:-"*    ,      r-.        r  ■ 


256  IRRITABILITY 

in  the  stretching  out  of  the  pseudopods  by  a  centrifugal  outflow- 
ing of  the  protoplasm  into  the  surrounding  medium,  the  contrac- 
tion phase  by  the  indrawing  of  the  pseudopods  by  the  centripetal 
inflowing  of  the  protoplasm  to  the  cell  body.  In  total  contraction, 
such  as  occurs,  for  instance,  in  strong  excitation  following  stimuli, 
the  cell  body  becomes  ball  shaped.  In  local  contraction  of  the 
long  thread  or  net-shaped  outstretched  pseudopods  of  the  sea 
rhizopoda,  the  protoplasm  of  the  retracting  pseudopod  forms  balls 
and  spindles.  Considered  from  a  physical  point  of  view  the 
expansion  phase  of  amoeboid  movement  is  an  expression  of  de- 
crease, the  contraction  phase  an  increase  of  the  surface  tension. 
I  have  shown  that  the  factor  which  under  physiological  conditions 
decreases  the  surface  pressure  and  thereby  brings  about  the 
expansion  phase  is  the  introduction  of  oxygen  into  the  living 
substance.  With  removal  of  oxygen  the  stretching  out  of  the 
pseudopods  ceases.  The  cell  gradually  draws  in  all  pseudopods 
and  assumes  the  shape  of  a  ball.  On  the  reintroduction  of  oxygen 
the  outflow  of  the  pseudopods  begins  anew.  This  fact  can  be 
observed  in  all  amoeboid  cells.  When,  therefore,  consumption  of 
oxygen  and  oxydative  changes  is  suppressed  during  narcosis  it  is 
to  be  expected  that  all  naked  protoplasm  masses  by  being  nar- 
cotized lose  their  capability  of  assuming  the  expansion  phase  of 
movement  and  contract  into  the  shape  of  balls.  Experimentation 
confirms  this  deduction  in  the  most  striking  manner.  When 
amoebae  are  placed  in  a  drop  of  water  under  the  microscope  in  a 
gas  cell  through  which  air  and  a  little  ether  are  allowed  to  flow, 
the  pseudopod  formation  of  the  amoebae  ceases  within  a  few 
minutes  and  they  all  assume  the  shape  of  a  ball.  (Figure  62.)  In 
asphyxiation  in  pure  nitrogen,  the  changes  in  the  amoebae  take 
place  in  exactly  the  same  manner  with  the  exception  that  in  this 
case  a  longer  period  ensues  according  to  the  size  and  activity  of 
the  animals.  About  20  to  60  minutes  elapse  before  depression 
becomes  complete.  If  larger  sea  rhizopoda  are  narcotized  in  the 
same  manner  all  pseudopods  are  more  or  less  retracted  and  the 
contained  protoplasm  flows  centripetally  and  contracts  in  the 
characteristic  manner  into  balls  and  spindles.  (Figure  63.)  If 
the  narcosis  is  removed  by  displacing  the  ether  by  pure  air,  the 


THE  PROCRSSRS  OR  DRPRl-.SSK  )\ 


strctcliin^r  out  of  the  i)scu(l()i)(,(ls  then  U-gins  anew,  provided  the 
narcosis  has  not  been  loo  deep  or  too  prolonged. 


C^ 


n 


n 


B 


Fifi.  62. 
Amoeba  Umax.     A     In  normal  state,     li    Narcotiicti  hy  rthrr. 


Til  the  face  of  all  this  evidence  there  can  he  nideed  no  further 
barrier  to  the  assumption  that  the  syinj)tonis  in  narcosis  are  a 
result  of  a  suppression  of  the  oxydative  i)rocesse.«i.  Neverthe- 
less, I  would  not  at  present  venture  to  maintain  that  tlu*  entrauvt- 
of  the  narcotic  into  livinj^  substance  produces  no  alterations  what- 
ever, except  just  this  oxydative  supi)ression.  lH)r  the  fircscnl 
it  seems  to  me  that   the  possibility  is  in  no  way  prechide<l  tlut 


258 


IRRITABILITY 


the  same  process,  which  is  expressed  in  the  oxydative  suppres- 
sion, is  connected  with  other  alterations  in  the  Hving  substance, 
of  which  we  are  as  yet  ignorant.  As  far  as  the  effects  of  larger 
doses  of  narcotics  are  concerned,  the  assumption  that  other 
alterations  take  place  in  the  living  substance  can  in  any  case 
hardly  be  avoided.  An  application  of  larger  quantities  of  nar- 
cotics brings  about  destruction  of  the  living  system  with  great 


Fig.  63. 
Rhizoplasma  Kaiseri.    Effect  of  chloroform. 


rapidity.  Here  the  alterations  in  the  optical  properties  of  the 
cell  are  of  such  magnitude  that  the  changes  are  directly  percep- 
tible under  the  microscope.  Bin^'^  has  observed  such  alterations 
in  the  nerve  cell  and  looked  upon  them  as  coagulation.  In  uni- 
cellular organisms  these  optical  alterations  can  readily  be  fol- 
lowed. If  amoebae,  sea  rhizopods  or  infusoria  are  narcotized 
with  stronger  doses  of  ether  or  chloroform,  the  protoplasm  be- 

1  Bins:  "Vorlesungen  uber   Pharmakologie  fur  Aerzte  und  Studierende."     II  Aufl. 
Berlin   1891. 


THE  PROCESSES  OF  DK PRI.SSION  t59 

comes  opaque  and  granulated,  it  a|»i)cars  darker  than   fonncrly 
and   in   many  cases  disi)lays  a  yellowish  brtiwii  color   in  trans- 
mitted light.     Cells  altered  in  this  way  no  longer  recover  afler 
removal  of  the  narcotic.     These  intense  and   rapidly  appearing 
alterations    of    protoplasm    resulting    from    the    application    of 
stronger  doses  of  the  narcotic  can  scarcely  Ik:  explained  as 
the  result  of  a  mere  decrease  of  the  oxydative  prcK-esses.      1 
would  seem  to  consist  rather,  as  suggested  hy  lUttz,  as  coag\: 
in  an  alteration  of  the  state  of  certain  com|K)nents  of  living 
stance.     Whether  these  alterations  arc  already  present  in  a  corre- 
spondingly slight  amount  in  those  degrees  of  narcosis  after  which 
complete   recovery  can   take   place  and    further  whether   in  this 
case  they  are  in  any  way  concerned  in  bringing  alx)Ut  the  indi- 
vidual  symptoms  of   the   foriuer.   are  (juestions  the  deci*»ion  of 
which    must    be    left    to    future    investigations,      llober^    indec<i 
makes  such  an  alteration  of  the  colloidal  state  of  the  : 
basis  of  a  theory  of  narcosis,     liut  such  assumptions  are  s 
more  than  speculations,      lliis  is  one  of  the  joints  in  which  our 
present  knowdedge  is  lacking. 

Even  if  we  restrict  ourselves  to  the  actually  established  altera- 
tions produced  by  the  narcotic  in  living  substance,  new  problems 
present  themselves,  the  investigation  of  which  recjuircs  funhcr 
effort.  Above  all,  the  question  arises  as  to  the  finer  mechanism  of 
oxydative  depression.  In  what  manner  does  the  narcotic  ni 
cule,  entering  into  the  living  substance.  su|)pre.ss  the  oxy<lalivc 
processes?  Here  there  are  very  dilVerent  possibilities  to  Ikt  taken 
into  consideration  and  up  to  the  present  in  our  investigations  of  a 
suppression  of  the  oxydative  processes  resulting  from  narcosis. 
we  have  stood  on  the  firm  ground  of  assured  facts.  However,  the 
discussion  of  the  nature  of  this  suppression  loads  u«i  into  the 
domain  of  hypothesis.  But  without  hy|>olhesis  there  can  Ikt  no 
progress  in  knowledge.  In  all  branches  of  scientific  re^icarch. 
working  hypotheses  are  required  for  the  obtainmcnt  of  new  fact*. 

On  closer  reflection,  there  are  chiefly  three  |>ossibiIitic«i.  which. 

1  Hbber:    "Bcitragc    zur    physikalischcn    Chcmie    dcr    Krrrciing    und    .!  w  " 

Pfliigcrs  Arch.   HH.   120.    1907.     The  vimc:   "I>.c   ;  '       '  slisc h  chrfm.chrn   \      ,      »c   4« 
Erregung."     Sammclrcfcrat.   Zcitschr.    f.   allgcm.    '  '     HJ     X.    I'lO 


260  IRRITABILITY 

considered  from  the  standpoint  of  our  present  knowledge  of  the 
processes  in  Hving  substance,  offer  an  explanation  of  the  oxyda- 
tive  suppression  as  a  result  of  narcosis. 

One  of  these  possibilities  is,  that  the  narcotic  itself  consumes 
the  oxygen  which  activates  living  substance  and  uses  it  for  its 
individual  oxydation,  so  that  the  specific  oxydable  material  of 
living  substance  receives  less  oxygen  from  the  oxygen  carriers. 
Based  on  a  series  of  interesting  experiments  this  view  has  been 
recently  maintained  by  Biirker}  He  observed  that  with  the 
electrolysis  of  acidulated  water,  to  which  a  small  per  cent,  of  ether 
was  added,  a  much  less  amount  of  oxygen  was  at  the  anode  than 
in  one  used  as  means  of  control,  containing  acidulated  water 
without  ether.  The  oxygen  was  replaced  at  the  anode  by 
oxydation  products  of  the  ether,  such  as  carbonic  oxide,  carbon 
dioxide,  acetate  aldehyde  and  acetic  acid.  In  experiments  with 
various  narcotics  he  likewise  found  that  the  stronger  the  effect 
produced  by  narcosis,  the  greater  the  oxygen  amount  required 
for  the  oxydation  taking  place  of  electrolysis.  Biirker  applies 
these  results  obtained  for  electrolysis  to  the  processes  in  living 
substance  and  takes  the  view  that  the  narcotic  seizes  on  the 
active  oxygen,  and  so  withdraws  it  from  the  masses  of  living  sub- 
stance possessing  a  great  oxygen  requirement.  It  cannot  be 
denied  that  this  conception  of  the  nature  of  certain  narcotics 
deserves  careful  investigation.  It  seems  to  me,  however,  that 
before  considering  it  in  the  light  of  a  serious  probability  a  grave 
difficulty  would  first  have  to  be  removed.  In  living  substance 
the  narcotic  would  occur  under  conditions  essentially  different 
from  those  existing  during  the  experiment  in  the  voltameter. 
In  the  former  case  there  would  be  the  struggle  for  oxygen 
of  the  specific  oxydable  cell  masses  to  be  met  with.  Considering 
the  small  amount  of  chemical  activity  of  the  greater  number  of 
narcotics  it  would  appear  at  least  doubtful  if  in  this  battle  for 
supremacy  the  latter  would  achieve  a  victory.  For  some  nar- 
cotics, as,  for  instance,  carbon  dioxide,  this  method  of  a  depres- 
sion of  the  oxydative  processes  would  have  no  bearing  whatever. 

1  Biirker:    "Eine    neue    Theorie    der    Narkose."      Miinchener    Med.    Wochenschrift, 
1910. 


TiiF.  i'R()c'i':ssi-:s  of  1)1-.i>ki:ssion 

This  is  ratlier  to  be  looked  for  in  llie  effects  of  oxydativc 

sion  of  the  aldehydes,  which  U'arhunf  has  recently  observed  and 

investigated.      Here,  however,  it   is  not  a  trtie  nnrrn«;i<  which  is 

concerned. 

A  second  possihilitv  of  a  ^u|>l)re^^l(.n  ot   oxvdauon  woiibl  \tc 
the  fixation  of  the  molecules  of  the  oxydable  substattcfs  by  chemi- 
cal or  f'hysical  cotnhinations  in  that  they  would  lose  their 
hility   of   oxydative   disintegration.      Such    a    su|)|h- 
however,  likewise  contain  hnt    few  elements  of  pr«.  ..».;. it .       A- 
has  been  shown,  an  anoxydative  breaking  down  continues  during 
narcosis,  wliich.  and  this  we  may  assume  with  certainly,  fumifthcn 
verv  different  i)r()ducts  in  great  varietv.     These  anoxvdalivc  dis- 
integration   i)roducts,   as   recovery   on   the   cessation  of   na- 
shows,  are  removed  during  recovery  by  oxydation.     If  the 
of  the  narcotic  consisted  in  the  prevention  in  spite  of  the  pr< 
of  oxygen  of  the  oxydation  by  combination,  it  would  Ikt  : 
sary  to  assume  that  the  narcotic  was  lK)und  to  a  mass  of  ctnn- 
pletely   heterogeneous   substances,   a  conclusion   we    >«h(m!f1    f*:nd 
difficult  to  entertain. 

If,  however,  depression  of  the  oxydative  processes  js  tuundcd 
neither  on  the  seizure  of  oxygen  by  the  narcotic  nor  the  fixation 
of  oxvdable  substances  bv  the  former,  there  remains  the  : 
bility  that  the  narcotic  suppresses  the  transmission  of  oxyijeti  to 
these  points  of  consumption.  We  assume  that  the  oxygen  trans- 
mission to  those  points  where  its  consumi>tion  takes  place  is  car- 
ried out  by  si)ecial  substances,  the  existence  of  which  lias  l>cen 
established  in  the  most  varied  vegetable  and  animal  cell  forms. 
Unfortunately  we  only  know  the^e  oxygen-carrying  substances 
by  their  effects.  (  )f  their  chemical  constitution  we  have  no 
knowledge,  but  we  usually  assume  that  the  transmission  of  ov 
gen  occurs   in   tlie  .same  manner  as   in  catalytic  priH  '  »n 

another   occasion    I    have    previously   exj)ressed    the 
that  the  narcotic  sui)pres.scs  oxydation  by  pnulucing  wv 
of  the  groups  acting  as  oxygen  carriers  to  carry  out  this  U\ 

1  IVarhurg:    "Ucbcr    BccinrtussnnB    dcr    Saucrtloffathmung.      II 
Bezichung  zvir  Constitution."     Zcitschr.   f.    ;  ' 

2  Max    I'crxvorn:   "L'cbcr    Narkosr."      !>>     '  '». 


262  IRRITABILITY 

tion.  If  we  assume  that  the  substances  possessing  the  character 
of  oxygen  carriers,  which  activate  the  molecular  oxygen  and  so 
render  it  capable  of  attacking  the  oxydable  substances,  lose  this 
capability  under  the  influence  of  narcotics,  this  supposition  would 
not  only  make  all  of  the  facts  of  suppression  of  oxygen  exchange 
in  narcosis  comprehensible,  considered  from  one  point,  but  like- 
wise, as  careful  investigation  has  shown,  be  in  complete  harmony 
with  all  knowledge  obtained  up  to  the  present  of  the  process  of 
narcosis. 

Here  is  the  point  where  the  interesting  observations  of  Hans 
Meyer'^  and  Overton^  on  the  relations  of  the  depressing  influence 
of  narcotics  to  their  solubility  of  fat  and  water  may  be  connected 
with  the  facts  of  the  suppression  of  oxydation.  Meyer  and  Over- 
ton have  quite  independently  of  each  other  made  the  same  obser- 
vation, that  the  depressing  effect  of  a  narcotic  is  the  greater,  the 
larger  the  coefficient  of  distribution  between  substances  of  a  fatty 
nature  and  water.  Those  narcotics  produce  the  strongest  effects 
which  are  readily  soluble  in  substances  of  a  fatty  nature,  but  not 
easily  so  in  water,  that  is,  in  which  the  coefficient  distri- 
bution between  fat  and  water  is  very  great.  This  law,  which 
has  been  demonstrated  by  Meyer  and  Overton  for  a  large  number 
of  narcotic  processes,  is  in  itself  not  a  theory  of  narcosis,  as 
has  been  often  erroneously  assumed.  It  shows  us,  however, 
an  important  condition,  which  must  be  considered  in  every 
theory  of  narcosis.  It  demonstrates  that  it  is  the  ease  with 
which  transmission  in  the  lipoid  occurs  which  allows  a  substance 
to  develop  narcotic  effects.  These  facts  would  seem  to  indicate 
that  the  lipoids  of  the  cell  are  connected  in  some  way  or  other 
with  the  exchange  of  oxygen.  If  we  assume  that  the  oxygen 
carriers,  the  chemical  constitution  of  which  is  so  far  not  known, 
bear  the  character  of  lipoids  and  belong,  say,  to  the  generally 
extended  group  of  phosphatides,  there  results  at  once  an  apparent 

1  Hans  Meyer:  "Welche  Eigenschaft  der  Anaesthetica  bedingt  ihre  narkotische 
Wirkung?"  Arch,  experimentelle  Pathol,  u.  Pharmacol.  Bd.  42,  1899.  Further:  Fritz 
Baum:  "Ein  physiologisch-chemischer  Beitrag  zur  Theorie  der  Narkotica."     Ibidem. 

2  Overton :  The  first  communication  of  the  results  obtained  by  Overton  were  made 
by  Rost:  "Zur  Theorie  der  Narkose"  in  the  Naturwiss.  Rundschau  Jarhrg.  1899. 
Overton  has  treated  the  subject  in  detail  in  his  work,  "Studien  iiber  die  Narkose 
zugleich  ein  Beitrag  zur  allgemeinen  Pharmakologie."     Jena   1901. 


THE  PROCESSES  OE  PEPRESSU^V  263 

connection  of  the  law  established  hy  .\feycr  and  Overt,  ,.  .s  iih  ihc 
nature  of  narcosis. 

The  depressing  effect  of  the  narcotic  would  ihcn  consist  m 
producing  incapa!)ility  of  the  lipoids  transmitting  oxygen  to  act 
as  carriers  of  the  same,  and  it  is,  tlKTcfore.  self-evident  that  the 
effect  of  the  narcotic  would  be  the  stronger  the  more  readily  it 
found  entrance  into  the  lii)oids.  It  is  i)crhaps  not  without  interest 
that  in  similar  manner  Mansfcld^  has  attempted  to  establish  a 
connection  between  the  facts  which  Meyer  and  Overton  have 
found  and  those  ascertained  by  my  coworkers  and  myself.  He 
expressed  the  view  that  the  lipoids  of  the  cells  represent  the 
channels  followed  by  the  oxygen  on  its  entrance,  and  that  in  c 
sequence  of  their  accunnilalion  in  the  lipoids,  the  narcotic;  bring 
about  asphyxiation  by  physically  obstructing  the  transii.  -i 
of  the  oxygen  from  the  outer  medium  thrcjugh  the  surface  layer 
of  the  lipoid  into  the  protoplasm.  The  divergence  in  our  views 
is  not  essential  in  their  nature,  and  I  attach  the  less  importance 
to  them  as  we  find  ourselves  here,  as  I  nuist  again  emphasize, 
on  purely  hypothetical  ground. 

In  consideration  of  these  observations  wc  may  jKrrhaps  est  ' 
lish  the  following  hypothesis  of  the  effect  of  the  oxydativc  sup- 
pression of  narcotics:  The  narcotics  obstruct,  either  by  absor]': 
or  loose  chemical  combination  the  oxygen  carriers  of  the  cell  and 
render  them  incapable  to  activate  the  molecular  oxygen.  In  con- 
sequence, oxydation  of  the  oxydable  substances  cannot  take  place 
and  disintegration  occurs  of  an  a«oxydative  form.  The  cell 
asphyxiates. 

In  conclusion  I  wish  to  warn  again.st  erroneous  assui 
that  all  oxydative  depressions  by  chemical  substances  are  MJr- 
cosis  and  that  the  mechanism  is  the  .same.  It  is  true  that  a  num- 
ber of  chemical  substances  depress  the  j^rocesscs  of  oxydation. 
But  the  latter  can  be  brought  about  in  very  varying  ways  I 
would  like  to  mention  the  effect  of  oxydative  depression  ^-: 
aldehydes.      To    this    Warbunf    has    added    hydrocyanic    acid, 

1  Mattsfcld:  "Narkosc   und   SaucrstoffmanRcl."     Prtintcr*  Arch.   Bd.    I?«.    I 

2  Warburg:    "Ucber     BccinfluMiinR    dcr     Saucrsloffalmunt.       II     ^' 
Beziehung  zur  Constitution."     Zcitwrhrift   f.   phyiiol.   Chemie   Bd.   71.    1911. 


264  IRRITABILITY 

arsenic  acid,  ammonia  and  substitution  compounds  of  ammonia. 
These  substances  do  not  follow  the  Meyer-Overton  law  of  the 
coefficient  of  distribution.  We  cannot  consider  them,  therefore, 
as  narcotics.  Future  investigation  will  establish  the  existence  of 
a  large  number  of  substances  belonging  to  this  great  group  of 
oxydation  suppressing  poisons,  which  are  not  narcotics.  And 
it  is  likewise  certain  that  depressing  substances  will  be  found,  the 
depressing  effects  of  which  will  not  have  their  point  of  attack  in 
the  oxygen  exchange,  but  will  be  shown  to  exist  in  other  con- 
stituents of  the  metabolic  chain.  Our  research  in  these  fields,  as 
already  said,  is  still  in  the  first  beginnings  and  its  perspective 
reaches  into  infinite  space. 


H 


! 


